Spirohydantoin Tricyclic CGRP Receptor Antagonists

ABSTRACT

Compounds of formula I: 
     
       
         
         
             
             
         
       
     
     (wherein variables A 1 , A 2 , A 3 , A 4 , A 5 , A 6 , A 7 , B 1 , B 2 , B 3 , B 4 , D 1 , D 2 , E 1 , E 2 , E 3 , E 4 , E 5 , G 1 , G 2 , R 6 , T, U, V, W, X, Y and Z are as described herein) which are antagonists of CGRP receptors and which are useful in the treatment or prevention of diseases in which the CGRP is involved, such as migraine. The invention is also directed to pharmaceutical compositions comprising these compounds and the use of these compounds and compositions in the prevention or treatment of such diseases in which CGRP is involved.

BACKGROUND OF THE INVENTION

CGRP (Calcitonin Gene-Related Peptide) is a naturally occurring 37-aminoacid peptide that is generated by tissue-specific alternate processingof calcitonin messenger RNA and is widely distributed in the central andperipheral nervous system. CGRP is localized predominantly in sensoryafferent and central neurons and mediates several biological actions,including vasodilation. CGRP is expressed in alpha- and beta-forms thatvary by one and three amino acids in the rat and human, respectively.CGRP-alpha and CGRP-beta display similar biological properties. Whenreleased from the cell, CGRP initiates its biological responses bybinding to specific cell surface receptors that are predominantlycoupled to the activation of adenylyl cyclase. CGRP receptors have beenidentified and pharmacologically evaluated in several tissues and cells,including those of brain, cardiovascular, endothelial, and smooth muscleorigin.

Based on pharmacological properties, these receptors are divided into atleast two subtypes, denoted CGRP₁ and CGRP₂. Human α-CGRP-(8-37), afragment of CGRP that lacks seven N-terminal amino acid residues, is aselective antagonist of CGRP₁, whereas the linear analogue of CGRP,diacetoamido methyl cysteine CGRP ([Cys(ACM)2,7]CGRP), is a selectiveagonist of CGRP₂. CGRP is a potent vasodilator that has been implicatedin the pathology of cerebrovascular disorders such as migraine andcluster headache. In clinical studies, elevated levels of CGRP in thejugular vein were found to occur during migraine attacks (Goadsby etal., Ann. Neurol., 1990, 28, 183-187). CGRP activates receptors on thesmooth muscle of intracranial vessels, leading to increasedvasodilation, which is thought to be the major source of headache painduring migraine attacks (Lance, Headache Pathogenesis: Monoamines,Neuropeptides, Purines and Nitric Oxide, Lippincott-Raven Publishers,1997, 3-9). The middle meningeal artery, the principle artery in thedura mater, is innervated by sensory fibers from the trigeminal ganglionwhich contain several neuropeptides, including CGRP. Trigeminal ganglionstimulation in the cat resulted in increased levels of CGRP, and inhumans, activation of the trigeminal system caused facial flushing andincreased levels of CGRP in the external jugular vein (Goadsby et al.,Ann. Neurol., 1988, 23, 193-196). Electrical stimulation of the duramater in rats increased the diameter of the middle meningeal artery, aneffect that was blocked by prior administration of CGRP(8-37), a peptideCGRP antagonist (Williamson et al., Cephalalgia, 1997, 17, 525-531).Trigeminal ganglion stimulation increased facial blood flow in the rat,which was inhibited by CGRP(8-37) (Escott et al., Brain Res. 1995, 669,93-99). Electrical stimulation of the trigeminal ganglion in marmosetproduced an increase in facial blood flow that could be blocked by thenon-peptide CGRP antagonist BIBN4096BS (Doods et al., Br. J. Pharmacol.,2000, 129, 420-423). Thus the vascular effects of CGRP may beattenuated, prevented or reversed by a CGRP antagonist.

CGRP-mediated vasodilation of rat middle meningeal artery was shown tosensitize neurons of the trigeminal nucleus caudalis (Williamson et al.,The CGRP Family: Calcitonin Gene-Related Peptide (CGRP), Amylin, andAdrenomedullin, Landes Bioscience, 2000, 245-247). Similarly, distentionof dural blood vessels during migraine headache may sensitize trigeminalneurons. Some of the associated symptoms of migraine, includingextra-cranial pain and facial allodynia, may be the result of sensitizedtrigeminal neurons (Burstein et al., Ann. Neurol. 2000, 47, 614-624). ACGRP antagonist may be beneficial in attenuating, preventing orreversing the effects of neuronal sensitization.

The ability of the compounds of the present invention to act as CGRPantagonists makes them useful pharmacological agents for disorders thatinvolve CGRP in humans and animals, but particularly in humans. Suchdisorders include migraine and cluster headache (Doods, Curr Opin InvesDrugs, 2001, 2 (9), 1261-1268; Edvinsson et al., Cephalalgia, 1994, 14,320-327); chronic tension type headache (Ashina et al., Neurology, 2000,14, 1335-1340); pain (Yu et al., Eur. J. Pharm., 1998, 347, 275-282);chronic pain (Hulsebosch et al., Pain, 2000, 86, 163-175); neurogenicinflammation and inflammatory pain (Holzer, Neurosci., 1988, 24,739-768; Delay-Goyet et al., Acta Physiol. Scanda. 1992, 146, 537-538;Salmon et al., Nature Neurosci., 2001, 4(4), 357-358); eye pain (May etal. Cephalalgia, 2002, 22, 195-196), tooth pain (Awawdeh et al., Int.Endocrin. J., 2002, 35, 30-36), non-insulin dependent diabetes mellitus(Molina et al., Diabetes, 1990, 39, 260-265); vascular disorders;inflammation (Zhang et al., Pain, 2001, 89, 265), arthritis, asthma(Foster et al., Ann. NY Acad. Sci., 1992, 657, 397-404; Schini et al.,Am. J. Physiol., 1994, 267, H2483-H2490; Zheng et al., J. Virol., 1993,67, 5786-5791); shock, sepsis (Beer et al., Crit. Care Med., 2002, 30(8), 1794-1798); opiate withdrawal syndrome (Salmon et al., NatureNeurosci., 2001, 4(4), 357-358) morphine tolerance (Menard et al., J.Neurosci., 1996, 16 (7), 2342-2351); hot flashes in men and women (Chenet al., Lancet, 1993, 342, 49; Spetz et al., J. Urology, 2001, 166,1720-1723); allergic dermatitis (Wallengren, Contact Dermatitis, 2000,43 (3), 137-143); encephalitis, brain trauma, ischaemia, stroke,epilepsy, and neurodegenerative diseases (Rohrenbeck et al., Neurobiol.of Disease 1999, 6, 15-34); skin diseases (Geppetti and Holzer, Eds.,Neurogenic Inflammation, 1996, CRC Press, Boca Raton, Fla.), neurogeniccutaneous redness, skin rosaceousness and erythema. Of particularimportance is the acute or prophylactic treatment of headache, includingmigraine and cluster headache.

The present invention relates to compounds that are useful as ligandsfor CGRP receptors, in particular antagonists for CGRP receptors,processes for their preparation, their use in therapy, pharmaceuticalcompositions comprising them and methods of therapy using them.

SUMMARY OF THE INVENTION

The present invention is directed to compounds of the formula I:

(wherein variables A¹, A², A³ A⁴, A⁵, A⁶, A⁷, B¹, B², B³, B⁴, D¹, D²,E¹, E², E³, E⁴, E⁵, G¹, G², R¹, T, U, V, W, X, Y and Z are as describedherein) which are antagonists of CGRP receptors and which are useful inthe treatment or prevention of diseases in which CGRP is involved, suchas migraine. The invention is also directed to pharmaceuticalcompositions comprising these compounds and the use of these compoundsand compositions in the prevention or treatment of such diseases inwhich CGRP is involved.

DETAILED DESCRIPTION OF THE INVENTION

The present invention is directed to compounds of the formula I:

wherein:A¹, A² and A³ are each independently selected from:

-   (1) a bond,-   (2) —CR¹³R¹⁴—, wherein R¹³ and R¹⁴ are each independently selected    from:    -   (a) hydrogen,    -   (b) C₁₋₆ alkyl, which is unsubstituted or substituted with 1-5        substituents each independently selected from:        -   (i) —C₃₋₆cycloalkyl,        -   (ii) —O—C₁₋₆alkyl,        -   (iii) halo,        -   (iv) hydroxy, and        -   (v) phenyl,    -   (c) hydroxy, and    -   (d) halo,-   (3) —NR¹⁰—,-   (4) —CR¹³R¹⁴—NR¹⁰—,-   (5) —CR¹³R¹⁴—CH₂—,-   (6) —CH₂—CR¹³R¹⁴—,-   (7) —O—C R¹³R¹⁴—,-   (8) —C R¹³R¹⁴—O—,-   (9) —C≡C—,-   (10) —C(R¹³)═C(R¹⁴)—, and-   (11) —C(═O)—,    where one or two of A¹, A² and A³ are optionally absent;    0-1 of A⁴, A⁵, A⁶ and A⁷ is selected from:-   (1) —O—,-   (2) —C(═O)—-   (3) —N(R¹⁵)—, wherein R¹⁵ is selected from:    -   (i) hydrogen,    -   (ii) C₁₋₆ alkyl, which is unsubstituted or substituted with 1-5        substituents where the substituents are each independently        selected from:        -   (a) hydroxy,        -   (b) —O—C₁₋₁₆alkyl,        -   (c) halo,        -   (d) —C₃₋₆cycloalkyl,        -   (e) trifluoromethyl, and        -   (f) phenyl,            where the remainder of A⁴, A⁵, A⁶ and A⁷ are each            independently selected from:-   (1) a bond, and-   (2) —CR¹³R¹⁴—,    where one or both of A⁴ and A⁷ are optionally absent;    B¹ and B⁴ are each independently selected from:-   (1)

-   (2)

-   (3)

B² and B³ are each independently selected from:

-   (1) a bond-   (2) ═C(R¹)—,-   (3) —C R¹R²—,-   (4) —C(═O)—,-   (5) —C(═S)—,-   (6) —C(═NR¹)—,-   (7) —N—,-   (8) —N(R¹)—,-   (9) —O—,-   (10) —S—, and-   (11) —SO₂—,    where one of B² and B³ is optionally absent;    D¹ and D² are each independently selected from:-   (1) ═C(R¹)—,-   (2) —C R¹R²—,-   (3) —C(═O)—,-   (4) —C(═S)—,-   (5) ═N—,-   (6) —N(R¹)—,-   (7) —O—,-   (8) —S—,-   (9) —SO₂—, and-   (10) —C(═NR¹)—;    E¹ and E⁵ are each independently selected from:-   (1) ═C(R⁴)—,-   (2) —C R⁴R⁵—,-   (3) —C(═O)—,-   (4) —C(═S)—,-   (5) ═N—,-   (6) ═N⁺(O—)—,-   (7) —N(R⁴)—,-   (8) —O—,-   (9) —S—, and-   (10) —SO₂—;    E³ and E⁴ are each independently selected from:-   (1) a bond,-   (2) ═C(R⁴)—,-   (3) —C R⁴R⁵—,-   (4) —C(═O)—,-   (5) —N—,-   (6) ═N⁺(O—)—,-   (7) —N(R⁴)—, and-   (8) —O—,    where one or both of E³ and E⁴ are optionally absent;    E² is selected from:-   (1)

-   (2)

-   and-   (3)

G¹ and G² are each independently selected from:

-   (1) ═C(R⁴)—,-   (2) —N—, and-   (3) ═N⁺(O—)—;    T, U and V are each independently selected from:-   (1) ═C(R¹)—, and-   (2) ═N—, and-   (3) ═N⁺(O⁻)—;-   wherein at least one of T, U, and V is ═C(R¹)—;    W, X, Y, and Z are each independently selected from:-   (1) a bond-   (2) ═C(R¹)—,-   (3) —C R¹R²—,-   (4) —C(═O)—,-   (5) —C(═S)—,-   (6) ═N—,-   (7) —N(R¹)—,-   (8) —O—,-   (9) —S—,-   (10) —S(O)—,-   (11) —SO₂—, and-   (12) —C(═NR¹)—-   where 1-4 of W, X, Y and Z are optionally absent;    R¹ and R² are each independently selected from:-   (1) hydrogen;-   (2) —C₁₋₆alkyl, which is unsubstituted or substituted with 1-7    substituents each independently selected from:    -   (a) halo,    -   (b) hydroxy,    -   (c) —O—C₁₋₁₆alkyl, which is unsubstituted or substituted with        1-5 halo,    -   (d) —C₃₋₆cycloalkyl,    -   (e) phenyl or heterocycle, wherein heterocycle is selected from:        azetidinyl, azepanyl, imidazolyl, oxazolyl, pyridinyl,        pyrimidinyl, pyrazinyl, pyridazinyl, piperidinyl, azepinyl,        piperazinyl, pyrazolyl, pyrrolidinyl, thiazolyl, thienyl,        triazolyl, tetrazolyl, tetrahydrofuryl, or morpholinyl,        -   which phenyl or heterocycle is unsubstituted or substituted            with 1-5 substituents each independently selected from:        -   (i) —C₁₋₆alkyl, which is unsubstituted or substituted with            1-5 halo,        -   (ii) —O—C₁₋₆alkyl, which is unsubstituted or substituted            with 1-5 halo,        -   (iii) halo,        -   (iv) hydroxy,        -   (v) oxo,        -   (vi) amino        -   (vii) phenyl, and        -   (viii) benzyl    -   (f) —CO₂R⁹, wherein R⁹ is independently selected from:        -   (i) hydrogen,        -   (ii) —C₁₋₆alkyl, which is unsubstituted or substituted with            1-6 substituents, substituents each independently selected            from:            -   (I) halo,            -   (II) hydroxy,            -   (III) —O—C₁₋₆alkyl, which is unsubstituted or                substituted with 1-5 halo,            -   (IV) —C₃₋₆cycloalkyl,            -   (V) phenyl, which is unsubstituted or substituted with                1-5 substituents each independently selected from:                -   (1) —C₁₋₄alkyl,                -   (2) —O—C₁₋₆alkyl,                -   (3) halo,                -   (4) trifluoromethyl, and                -   (5) —OCF₃,        -   (iii) —C₃₋₆cycloalkyl, which is unsubstituted or substituted            with 1-5 halo, and        -   (iv) phenyl or heterocycle, wherein heterocycle is selected            from: pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl,            thienyl, pyrrolidinyl, thiazolyl, oxazolyl, imidazolyl,            triazolyl, tetrazolyl, benzimidazolyl, benzothiazolyl,            benzoxazolyl, imidazolinyl, indolinyl, indolyl, quinolinyl,            isoquinolinyl, tetrahydroquinolinyl, isoindolinyl,            tetrahydroisoquinolinyl, tetrahydrofuryl, quinoxalinyl,            piperidinyl, piperazinyl, and morpholinyl, which phenyl or            heterocycle is unsubstituted or substituted with 1-5            substituents each independently selected from:            -   (I) halo,            -   (II) —C₁₋₆alkyl, which is unsubstituted or substituted                with 1-5 halo            -   (III) —O—C₁₋₆alkyl, which is unsubstituted or                substituted with 1-5 halo            -   (IV) —C₃₋₆cycloalkyl,            -   (V) oxo,            -   (VI) —CN,            -   (VII) hydroxy, and            -   (VIII) phenyl,    -   (g) —NR¹⁰R¹¹, wherein R¹⁰ and R¹¹ are each independently        selected from:        -   (i) hydrogen,        -   (ii) —C₁₋₆alkyl, which is unsubstituted or substituted with            1-6 substituents each independently selected from:            -   (I) —O—C₁₋₆alkyl,            -   (II) halo,            -   (III) hydroxy,            -   (IV) —OCF₃,            -   (V) —C₃₋₆cycloallyl, and            -   (VI) phenyl,        -   (iii) —C₄₋₆cycloalkyl,        -   (iv) phenyl, which is unsubstituted or substituted with 1-5            substituents where the substituents are independently            selected from:            -   (I) —C₁₋₆alkyl,            -   (II) —O—C₁₋₆alkyl,            -   (III) halo,            -   (IV) hydroxy,            -   (V) trifluoromethyl,            -   (VI) —OCF₃, and            -   (VII) CN, and        -   (v) benzyl, which is unsubstituted or substituted with 1-5            substituents where the substituents are independently            selected from:            -   (I) —C₁₋₆alkyl,            -   (II) —O—C₁₋₆alkyl,            -   (III) halo, and            -   (IV) trifluoromethyl,        -   (vi) —COR⁹, and        -   (vii) —SO₂R¹²,    -   (h) —SO₂R¹², wherein R¹² is selected from:        -   (i) —C₁₋₆alkyl, which is unsubstituted or substituted with            1-6 fluoro,        -   (ii) —C₃₋₆cycloalkyl,        -   (iii) phenyl or heterocycle, wherein heterocycle is selected            from: pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl,            piperidinyl, piperazinyl, pyrrolidinyl, thienyl, or            morpholinyl, which phenyl or heterocycle is unsubstituted or            substituted with 1-5 substituents independently selected            from:            -   (I) —C₁₋₆alkyl,            -   (II) —O—C₁₋₆alkyl,            -   (III) halo,            -   (IV) hydroxy,            -   (V) trifluoromethyl,            -   (VI) —OCF₃, and            -   (VII) CN, and        -   (iv) benzyl, which is unsubstituted or substituted with 1-5            substituents independently selected from:            -   (I) —C₁₋₆alkyl,            -   (II) —O—C₁₋₆alkyl,            -   (III) halo, and            -   (IV) trifluoromethyl,    -   (i) —CONR^(10a)R^(11a), wherein R^(10a) and R^(11a) are each        independently selected from:        -   (i) hydrogen,        -   (ii) —C₁₋₆alkyl, which is unsubstituted or substituted with            1-6 substituents each independently selected from:            -   (I) —O—C₁₋₆alkyl, which is unsubstituted or substituted                with 1-5 halo,            -   (II) halo,            -   (III) hydroxy,            -   (IV) —OCF₃,            -   (V) —C₃₋₆cycloalkyl, and            -   (VI) phenyl,        -   (iii) —C₅₋₆cycloalkyl,        -   (iv) phenyl, which is unsubstituted or substituted with 1-5            substituents where the substituents are independently            selected from:            -   (I) —C₁₋₆alkyl, which is unsubstituted or substituted                with 1-5 halo,            -   (II) —O—C₁₋₆alkyl, which is unsubstituted or substituted                with 1-5 halo,            -   (III) halo,            -   (IV) hydroxy,            -   (V) trifluoromethyl,            -   (VI) —OCF₃, and            -   (VII) CN, and        -   (v) benzyl, which is unsubstituted or substituted with 1-5            substituents where the substituents are independently            selected from:            -   (I) —C₁₋₆alkyl, which is unsubstituted or substituted                with 1-5 halo,            -   (II) —O—C₁₋₆alkyl, which is unsubstituted or substituted                with 1-5 halo,            -   (III) halo, and            -   (IV) trifluoromethyl,        -   or where R^(10a) and R^(11a) join to form a ring selected            from azetidinyl, pyrrolidinyl, piperidinyl, azepanyl,            piperazinyl, or morpholinyl, which ring is unsubstituted or            substituted with 1-5 substituents each independently            selected from:            -   (I) —C₁₋₆alkyl, which is unsubstituted or substituted                with 1-5 halo,            -   (II) —O—C₁₋₆alkyl, which is unsubstituted or substituted                with 1-5 halo,            -   (III) halo,            -   (IV) hydroxy,            -   (V) phenyl,            -   (VI) benzyl,            -   (VII) —COR⁹, and            -   (VIII) —SO₂R¹²    -   (j) trifluoromethyl,    -   (k) —OCO₂R⁹,    -   (l) (NR^(10a))CO₂R⁹,    -   (m) —O(CO)NR^(10a)R^(11a),    -   (n) —(NR⁹)(CO)NR^(10a)R^(11a),    -   (O)—O—C₃₋₆cycloallyl,    -   (p) —SO₂NR^(10a)R^(11a), and    -   (q) —CN,-   (3) —C₃₋₆cycloalkyl, which is unsubstituted or substituted with 1-7    substituents each independently selected from:    -   (a) halo,    -   (b) hydroxy,    -   (c) —O—C₁₋₆alkyl, which is unsubstituted or substituted with 1-5        halo,    -   (d) —C₁₋₆alkyl, which is unsubstituted or substituted with 1-5        halo,    -   (e) phenyl, which is unsubstituted or substituted with 1-5        substituents each independently selected from:        -   (i) —C₁₋₆alkyl,        -   (ii) —O—C₁₋₆alkyl,        -   (iii) halo,        -   (iv) hydroxy, and        -   (v) trifluoromethyl,-   (4) phenyl or heterocycle, wherein heterocycle is selected from:    pyridinyl, pyrimidinyl, pyrazinyl, thienyl, pyridazinyl,    pyrrolidinyl, azetidinyl, azepanyl, thiazolyl, isothiazolyl,    oxazolyl, isoxazolyl, imidazolyl, triazolyl, tetrazolyl, azepinyl,    benzimidazolyl, benzopyranyl, benzofuryl, benzothiazolyl,    benzoxazolyl, chromanyl, furyl, imidazolinyl, indolinyl, indolyl,    quinolinyl, isoquinolinyl, tetrahydroquinolinyl, isoindolinyl,    tetrahydroisoquinolinyl, 2-oxopiperazinyl, 2-oxopiperidinyl,    2-oxopyrrolidinyl, pyrazolidinyl, pyrazolyl, pyrrolyl, quinazolinyl,    tetrahydrofuryl, thiazolinyl, purinyl, naphthyridinyl, quinoxalinyl,    1,3-dioxolanyl, oxadiazolyl, piperidinyl, tetrahydropyranyl,    tetrahydrothienyl, tetrahydrothiopyranyl, and morpholinyl, which    phenyl or heterocycle is unsubstituted or substituted with 1-5    substituents each independently selected from:    -   (a) —C₁₋₆alkyl, which is unsubstituted or substituted with 1-5        substituents where the substituents are each independently        selected from:        -   (i) halo,        -   (ii) hydroxy,        -   (iii) —O—C₁₋₆alkyl, which is unsubstituted or substituted            with 1-5 halo,        -   (iv) —C₃₋₆cycloalkyl,        -   (v) phenyl,        -   (vi) —CO₂R⁹, and        -   (vii) —NR¹⁰R¹¹,    -   (b) halo,    -   (c) hydroxy,    -   (d) —O—C₁₋₆alkyl, which is unsubstituted or substituted with 1-6        fluoro,    -   (e) —C₃₋₆cycloalkyl,    -   (f) phenyl or heterocycle, wherein heterocycle is selected from:        pyrrolidinyl, piperidinyl, piperazinyl, pyridinyl, pyrimidinyl,        pyrazinyl, thienyl, or morpholinyl, which phenyl or heterocycle        is unsubstituted or substituted with 1-substituents each        independently selected from:        -   (i) —C₁₋₆alkyl, which is unsubstituted or substituted with            1-5 halo,        -   (ii) —O—C₁₋₆alkyl, which is unsubstituted or substituted            with 1-5 halo,        -   (iii) halo,        -   (iv) hydroxy, and        -   (v) trifluoromethyl,    -   (g) —CO₂R⁹,    -   (h) —(CO)R⁹,    -   (i) —NR¹⁰R¹¹,    -   (j) —CONR^(10a)R^(11a),    -   (k) oxo    -   (l) —SR¹²,    -   (m) —S(O)R¹²,    -   (n) —SO₂R¹²,    -   (o) —CN and    -   (p) —SO₂NR^(10a)R^(11a),-   (5) halo,-   (6) oxo,-   (7) hydroxy,-   (8) —O—C₁₋₆alkyl, which is unsubstituted or substituted with 1-5    substituents where the substituents are each independently selected    from:    -   (a) halo,    -   (b) hydroxy,    -   (c) —C₃₋₆cycloalkyl,    -   (d) phenyl,    -   (e) —CO₂R⁹, and    -   (f) —NR¹⁰R¹¹,-   (9) —CN,-   (10) —CO₂R⁹,-   (11) —NR¹⁰R¹¹,-   (12) —SR¹²,-   (13) —S(O)R¹²,-   (14) —SO₂R¹²,-   (15) —SO₂NR^(10a)R^(11a),-   (16) —CONR^(10a)R^(11a),-   (17) —OCO₂R⁹,-   (18) (NR^(10a))CO₂R⁹,-   (19) —O(CO)NR^(10a)R^(11a),-   (20) —(NR⁹)(CO)NR^(10a)R^(11a),-   (21) —(CO)—(CO)NR^(10a)R^(11a), and-   (22) —(CO)—(CO)OR⁹;    R⁴ and R⁵ are each independently selected from:-   (1) hydrogen;-   (2) —C₁₋₄alkyl, which is unsubstituted or substituted with 1-5    substituents each independently selected from:    -   (a) halo,    -   (b) hydroxy,    -   (c) —O—C₁₋₆alkyl, which is unsubstituted or substituted with 1-5        halo,    -   (d) —C₃₋₆cycloalkyl,    -   (e) phenyl,    -   (f) —CO₂R⁹,    -   (g) —NR¹⁰R¹¹, and    -   (h) —CONR^(10a)R^(11a)-   (3) —C₃₋₆cycloalkyl,-   (4) phenyl, which is unsubstituted or substituted with 1-3    substituents where the substituents are each independently selected    from:    -   (a) —C₁₋₄alkyl, which is unsubstituted or substituted with 1-3        halo,    -   (b) halo,    -   (c) hydroxy, and    -   (d) —O—C₁₋₄alkyl, which is unsubstituted or substituted with 1-6        halo,-   (5) halo,-   (6) hydroxy,-   (7) —O—C₁₋₁₆alkyl, which is unsubstituted or substituted with 1-5    halo,-   (8) —CN,-   (9) —CO₂R⁹,-   (10) —NR¹⁰R¹¹,-   (11) —SO₂R¹²,-   (12) —CONR^(10a)R^(11a),-   (13) —OCO₂R⁹, and-   (14) —(NR^(10a))CO₂R⁹;    R⁶ is selected from:-   (1) hydrogen,-   (2) —C₁₋₆alkyl or —C₃₋₆cycloalkyl which are unsubstituted or    substituted with 1-7 substituents each independently selected from:    -   (a) halo,    -   (b) hydroxy,    -   (c) —O—C₁₋₆alkyl,    -   (d) —C₃₋₆cycloallyl,    -   (e) phenyl, which is unsubstituted or substituted with 1-5        substituents each independently selected from:        -   (i) —C₁₋₆alkyl,        -   (ii) —O—C₁₋₁₆alkyl,        -   (iii) halo,        -   (iv) hydroxy, and        -   (v) trifluoromethyl,    -   (f) —CO₂R⁹,    -   (g) —NR¹⁰R¹¹,    -   (h) —CONR¹⁰R¹¹,    -   (i) —SO₂R¹², and    -   (j) trifluoromethyl-   (3) phenyl or heterocycle, wherein heterocycle is selected from:    pyridinyl, pyrimidinyl, pyrazinyl, thienyl, or morpholinyl, which    phenyl or heterocycle is unsubstituted or substituted with 1-5    substituents each independently selected from:    -   (a) —C₁₋₆alkyl,    -   (b) —O—C₁₋₆alkyl,    -   (c) halo,    -   (d) hydroxy, and    -   (e) trifluoromethyl;        and pharmaceutically acceptable salts thereof and individual        enantiomers and diastereomers thereof.

In embodiments of the invention where R⁶ is methyl, A¹ is CR¹³R¹⁴—, A²,A³, A⁴ and A⁷ are absent, A⁵ and A⁶ are CH₂—, G¹ and G² are ═C(R⁴)—, E¹is ═N—, E² is

E³ and E³ are ═C(H)—, and B⁴ is absent, the following structure forms:

In embodiments of the invention where R⁶ is methyl, A¹ is —C(═O)—, A²,A³, A⁴ and A⁷ are absent, A⁵ and A⁶ are —CH₂—, G¹ and G² are ═C(R⁴)—, E¹is ═N—, E² is

E³ and E⁵ are ═C(H)—, and E⁴ is absent, the following structure forms:

In embodiments of the invention where R⁶ is methyl, A¹ is CR¹³R¹⁴, A²,A³, A⁴ and A⁷ are absent, A⁵ and A⁶ are CH₂—, G¹ and G² are ═C(R⁴)—, E¹and E⁵ are ═N—, E² is

E³ is ═C(H)—, and E⁴ is absent, the following structure forms:

In embodiments of the invention where R⁶ is methyl, A¹ is CR¹³R¹⁴, A²,A³, A⁴ and A⁷ are absent, A⁵ and A⁶ are —CH₂—, G¹ and G² are ═C(R⁴)—, E¹is —N(R⁴)—, E² is

E³ and E⁴ are absent, and E⁵ is ═N—, the following structure forms:

In embodiments of the invention where R⁶ is methyl, A¹ is CR¹³R¹⁴—, A²,A³, A⁴ and A⁷ are absent, A⁵ and A⁶ are CH₂—, G¹ and G² are ═C(R⁴)—, E¹is —N(H)—, E² is

E³ is ═N—, E⁴ and E⁵ are —CR⁴R⁵—, the following structure forms:

In embodiments of the invention where B⁴ is

B² is —C(═O)—, B³ is absent, B¹ is

D¹ is —CR¹R²—, D² is —N(R¹)—, W is —C(═O)—, X, Y and Z are absent, andT, U and V are ═C(R¹)—, the following structure forms:

In embodiments of the invention where B⁴ is

B² is —C(═O)—, B³ is absent, B¹ is

D¹ is —CR¹R²—, D² is —N(R¹)—, W is C(═O)—, X, Y and Z are absent, and T,U and V are ═C(R¹)—, the following structure forms:

In embodiments of the invention where B⁴ is

B² is —CR¹R²—, B³ is absent, B¹ is

D¹ is —CR¹R²—, D² is —N(R¹)—, W is —C(═O)—, X, Y and Z are absent, andT, U and V are ═C(R¹), the following structure forms:

In embodiments of the invention where B⁴ is

B² is ═C(R¹)—, B³ is absent, B¹ is

D¹ is —CR¹R²—, D² is —N(R¹)—, W is C(═O)—, X, Y and Z are absent, and T,U and V are ═C(R¹)—, the following structure forms:

In embodiments of the invention where B⁴ is

B² is ═C(R¹)—, B³ is absent, B¹ is

D¹ is —R¹R²—, D² is —N(R¹)—, W is C(═O)—, X, Y and Z are absent, and T,U and V are ═C(R¹)—, the following structure forms:

In embodiments of the invention where B⁴ is

B² is ═C(R¹)—, B³ is absent, B¹ is

D² is —CR¹R²—, D¹ is —N(R¹)—, W is —C(═O)—, X, Y and Z are absent, andT, U and V are ═C(R¹)—, the following structure forms:

In embodiments of the invention where B⁴ is

B² is —C(═O)—, B³ is absent, B¹ is

D¹ is —R¹R²—, D² is —N(R¹)—, W is —C(═O)—, X, Y and Z are absent, and Tand V are ═C(R¹)—, and U is ═N—, the following structure forms:

In embodiments of the invention where B⁴ is

B² is —C(O)—, B³ is absent, B¹ is

D¹ is —CR¹R²—, D² is —N(R¹)—, W is —C(═O)—, X, Y and Z are absent, and Uand V are ═C(R¹)—, and T is ═N—, the following structure forms:

In embodiments of the invention where B⁴ is

B² is C(═O)—, B³ is absent, B¹ is

D¹ is ═C(R¹)—, D² is —N(R¹)—, W is C(═O)—, X, Y and Z are absent, and T,U and V are ═C(R¹)—, the following structure forms:

In embodiments of the invention where B⁴ is

B³ is C(═O)—, B² is ═C(R¹)—, B¹ is

D¹ is —C(═O)—, D² is —N(R¹)—, W, X, Y and Z are absent, and T, U and Vare ═C(R¹)—, the following structure forms:

In embodiments of the invention where B⁴ is

B² is —C(═O)—, B³ is absent, B¹ is

D¹ is —R¹R²—, D² is —N(R¹)—, W is absent, X and Y are —R¹R²—, Z is—C(═O)—, and T, U and V are ═C(R¹)—, the following structure forms:

In embodiments of the invention where B⁴ is

B² is —R¹R²—, B³ is absent, B¹ is

D¹ is —CR¹R²—, D² is —N(R¹)—, W is absent, X and Y are —R¹R²—, Z isC(═O)—, and T, U and V are ═C(R¹)—, the following structure forms:

In embodiments of the invention where B⁴ is

B² is —CR¹R²—, B³ is absent, B¹ is

D¹ is —R¹R²—, D² is —N(R¹)—, W and X are absent, Y is —CR¹R²—, Z is—C(═O)—, and T, U and V are ═C(R¹)—, the following structure forms:

In embodiments of the invention where B⁴ is

B² is ═C(R¹)—, B³ is absent, B¹ is

D¹ is CR¹R²—, D² is —N(R¹)—, W and X are absent, Y is —CR¹R²—, Z isC(═O)—, and T, U and V are ═C(R¹)—, the following structure forms:

An embodiment of the present invention includes compounds of the formulaIa:

wherein A¹, A⁴, A⁵, A⁶, A⁷, B¹, B², B³, B⁴, D¹, D², E¹, E², E³, E⁴, E⁵,T, U, V, W, X, Y, Z, R⁴ and R⁶ are defined herein; and pharmaceuticallyacceptable salts thereof and individual enantiomers and diastereomersthereof.

Another embodiment of the present invention includes compounds of theformula Ib:

wherein A¹, B¹, B², B³, B⁴, D¹, D², E¹, E², E³, E⁴, E⁵, T, U, V, X, Y,Z, R⁴ and R⁶ are defined herein; and pharmaceutically acceptable saltsthereof and individual enantiomers and diastereomers thereof.

Another embodiment of the present invention includes compounds of theformula Ic:

wherein A¹, B¹, B², B⁴, D¹, D², E¹, E², E³, E⁵, T, U, V, X, Y, Z, R⁴ andR⁶ are defined herein; and pharmaceutically acceptable salts thereof andindividual enantiomers and diastereomers thereof.

Another embodiment of the present invention includes compounds of theformula Id:

wherein B¹, B², B⁴, D¹, D², E³, E⁵, T, U, V, X, Y, Z, R⁴ and R⁶ aredefined herein;and pharmaceutically acceptable salts thereof and individual enantiomersand diastereomers thereof.

Another embodiment of the present invention includes compounds of theformula Ie:

wherein B¹, B², B³, D¹, E³, E⁵, T, U, V, X, Y, R¹, R⁴, and R⁶ aredefined herein; and pharmaceutically acceptable salts thereof andindividual enantiomers and diastereomers thereof.

In an embodiment of the present invention A¹ is CH₂.

In an embodiment of the present invention A¹ is C(═O)—.

In an embodiment of the present invention A² is a bond.

In an embodiment of the present invention A³ is a bond.

In an embodiment of the present invention A⁴ is selected from: CH₂; anda bond.

In an embodiment of the present invention A⁴ is a bond.

In an embodiment of the present invention A⁵ is CH₂.

In an embodiment of the present invention A⁶ is CH₂.

In an embodiment of the present invention A⁷ is selected from: CH₂; anda bond.

In an embodiment of the present invention A⁷ is a bond.

In an embodiment of the present invention B¹ is selected from:

wherein R¹ is defined herein.

In an embodiment of the present invention B⁴ is selected from:

In an embodiment of the present invention B⁴ is

In an embodiment of the present invention B² is selected from: ═C(R¹)—;—CR¹, R²—; and —C(═O)—; wherein R¹ and R² are defined herein.

In an embodiment of the present invention B² is selected from: ═C(H)—;—CH₂—; and —C(═O)—.

In an embodiment of the present invention B³ is selected from: ═C(H)—;—CH₂—; and —C(═O)—; and a bond.

In an embodiment of the present invention B³ is a bond.

In an embodiment of the present invention D¹ is selected from: ═C(R¹)—;—CR¹R²—; —C(═O)—; and —N(R¹)—; wherein R¹ and R² are defined herein.

In an embodiment of the present invention D¹ is selected from: ═C(H)—;—CH₂—; —C(═O)—; and —N(H)—.

In an embodiment of the present invention D¹ is —CH₂—.

In an embodiment of the present invention D² is selected from:

—CR¹R²—; and —N(R¹)—; wherein R¹ and R² are defined herein.

In an embodiment of the present invention D² is selected from: —CH₂—;—N(H)—; and —N(Me)—.

In an embodiment of the present invention D² is —N(H)—.

In an embodiment of the present invention E¹ is selected from: ═C(R⁴)—;—CR⁴R⁵—; ═N—; and —N(R⁴)—; wherein R⁴ and R⁵ are defined herein.

In an embodiment of the present invention E¹ is selected from: ═N—; and—N(H)—.

In an embodiment of the present invention E⁵ is selected from: ═C(R⁴)—;—CR⁴R⁵—; ═N—; and —N(R⁴)—; wherein R⁴ and R⁵ are defined herein.

In an embodiment of the present invention E⁵ is selected from: ═C(H)—;—CH₂—; ═N—; and —N(H)—.

In an embodiment of the present invention E³ is selected from:

a bond; ═C(R⁴)—; —CR⁴R⁵—; ═N—; and —N(R⁴)—; wherein R⁴ and R⁵ aredefined herein.

In an embodiment of the present invention E³ is selected from:

a bond; ═C(H)—; ═N—; and —N(H)—.

In an embodiment of the present invention E⁴ is selected from:

a bond; and —CH₂—.

In an embodiment of the present invention E⁴ is a bond.

In an embodiment of the present invention E² is selected from:

In an embodiment of the present invention E² is

In an embodiment of the present invention G¹ is ═C(R⁴)—; wherein R⁴ isdefined herein.

In an embodiment of the present invention G¹ is ═C(H)—.

In an embodiment of the present invention G² is ═C(R⁴)—; wherein R⁴ isdefined herein.

In an embodiment of the present invention G² is ═C(H)—.

In an embodiment of the present invention T is selected from: ═C(R¹)—;and ═N—; wherein R¹ is defined herein.

In an embodiment of the present invention T is selected from: ═C(H)—;and ═N—.

In an embodiment of the present invention U is selected from: ═C(R¹)—;and ═N—; wherein R¹ is defined herein.

In an embodiment of the present invention U is selected from: ═C(H)—;═C(Me)—; and —N—.

In an embodiment of the present invention V is ═C(H)—.

In an embodiment of the present invention W is selected from:

a bond; —CR¹R²—; and —C(═O)—; wherein R¹ and R² are defined herein.

In an embodiment of the present invention W is selected from:

a bond; —CH₂—; and —C(═O)—.

In an embodiment of the present invention W is —C(═O)—.

In an embodiment of the present invention W is a bond.

In an embodiment of the present invention X is selected from:

a bond; —CR¹R²—; and —C(═O)—; wherein R¹ and R² are defined herein.

In an embodiment of the present invention X is selected from:

a bond; —CH₂—; and —C(═O)—.

In an embodiment of the present invention X is a bond.

In an embodiment of the present invention Y is selected from:

a bond; —CR¹R²—; and —C(═O)—; wherein R¹ and R² are defined herein.

In an embodiment of the present invention Y is selected from:

a bond; —CH₂—; and —C(═O)—.

In an embodiment of the present invention Y is a bond.

In an embodiment of the present invention Z is selected from:

a bond; —CR¹R²—; and —C(═O)—; wherein R¹ and R² are defined herein.

In an embodiment of the present invention Z is —C(═O)—.

In an embodiment of the present invention Z is a bond.

In an embodiment of the present invention R¹ and R² are independentlyselected from:

-   -   (1) hydrogen;    -   (2) —C₁₋₆alkyl, which is unsubstituted or substituted with 1-5        substituents each independently selected from:        -   (a) halo,        -   (b) hydroxy,        -   (c) —O—C₁₋₆alkyl, which is unsubstituted or substituted with            1-3 fluoro,        -   (d) —C₃₋₆cycloalkyl,        -   (e) phenyl or heterocycle, wherein heterocycle is selected            from: azetidinyl, imidazolyl, oxazolyl, pyridinyl,            pyrimidinyl, pyrazinyl, piperidinyl, piperazinyl,            pyrrolidinyl, thiazolyl, thienyl, triazolyl, tetrazolyl,            tetrahydrofuryl, or morpholinyl, which phenyl or heterocycle            is unsubstituted or substituted with 1-3 substituents each            independently selected from:            -   (i) —C₁₋₄alkyl, which is unsubstituted or substituted                with 1-3 fluoro,            -   (ii) —O—C₁₋₄alkyl, which is unsubstituted or substituted                with 1-3 fluoro,            -   (iii) halo,            -   (iv) hydroxy,        -   (v) trifluoromethyl, and            -   (vi) —OCF₃,        -   (f) —CO₂R⁹,        -   (g) —NR¹⁰R¹¹,        -   (h) —CONR^(10a)R^(11a),        -   (i) —(NR^(10a))CO₂R⁹, and        -   (j) —(NR⁹)(CO)NR^(10a)R^(11a);    -   (3) —C₃₋₆cycloalkyl, which is unsubstituted or substituted with        1-3 substituents each independently selected from:        -   (a) halo,        -   (b) hydroxy,        -   (c) —C₁₋₆alkyl, and        -   (d) —O—C₁₋₆alkyl,    -   (4) phenyl or heterocycle, wherein heterocycle is selected from:        pyridinyl, pyrimidinyl, pyrazinyl, thienyl, pyrrolidinyl,        azetidinyl, thiazolyl, oxazolyl, isoxazolyl, imidazolyl,        triazolyl, tetrazolyl, benzimidazolyl, benzoxazolyl,        imidazolinyl, indolinyl, indolyl, quinolinyl, isoquinolinyl,        tetrahydroquinolinyl, isoindolinyl, tetrahydroisoquinolinyl,        2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl,        quinazolinyl, tetrahydrofuryl, naphthyridinyl, quinoxalinyl,        1,3-dioxolanyl, oxadiazolyl, piperidinyl, tetrahydropyranyl, and        morpholinyl, which phenyl or heterocycle is unsubstituted or        substituted with 1-3 substituents each independently selected        from:        -   (a) —C₁₋₄alkyl, which is unsubstituted or substituted with            1-3 fluoro,        -   (b) halo,        -   (c) hydroxy,    -   (d) —O—C₁₋₄alkyl, which is unsubstituted or substituted with 1-6        fluoro,    -   (e) —C₃₋₆cycloalkyl,    -   (g) —CO₂R⁹,    -   (h) —NR¹⁰R¹¹, and    -   (i) —CONR^(10a)R^(11a),    -   (5) halo,    -   (6) hydroxy,    -   (7) —O—C₁₋₄alkyl, which is unsubstituted or substituted with 1-3        halo,    -   (8) —CN,    -   (9) —CO₂R⁹,    -   (10) —NR¹⁰R¹¹,    -   (11) —CONR^(10a)R^(11a) and    -   (12) —(NR^(10a))CO₂R⁹.

In an embodiment of the present invention R¹ and R² are independentlyselected from:

-   -   (1) hydrogen;    -   (2) —C₁₋₄alkyl, which is unsubstituted or substituted with 1-3        substituents each independently selected from:        -   (a) halo,        -   (b) —O—C₁₋₄alkyl,        -   (c) phenyl or heterocycle, wherein heterocycle is selected            from: azetidinyl, oxazolyl, pyridinyl, pyrimidinyl,            pyrazinyl, piperidinyl, piperazinyl, pyrrolidinyl,            tetrahydrofuryl, or morpholinyl, which phenyl or heterocycle            is unsubstituted or substituted with 1-3 substituents each            independently selected from:            -   (i) —C₄alkyl,            -   (ii) —O—C₁₋₄alkyl,            -   (iii) halo, and            -   (iv) hydroxy,        -   (d) —CO₂R⁹,        -   (e) —NR¹⁰R¹¹,        -   (f) —CONR^(10a)R^(11a),    -   (3) —C₃₋₆cycloallyl,    -   (4) phenyl or heterocycle, wherein heterocycle is selected from:        pyridinyl, pyrimidinyl, pyrazinyl, pyrrolidinyl, azetidinyl,        oxazolyl, imidazolyl, 2-oxopiperazinyl, 2-oxopiperidinyl,        2-oxopyrrolidinyl, tetrahydrofuryl, oxadiazolyl, piperidinyl,        and morpholinyl, which phenyl or heterocycle is unsubstituted or        substituted with 1-3 substituents each independently selected        from:        -   (a) —C₁₋₄alkyl, which is unsubstituted or substituted with            1-3 fluoro,        -   (b) halo,        -   (c) hydroxy,        -   (d) —O—C₁₋₄alkyl,        -   (e) —C₃₋₆cycloalkyl,        -   (f) —NR¹⁰R¹¹, and        -   (g) —CONR¹⁰R¹¹,    -   (5) halo,    -   (6) hydroxy,    -   (7) —O—C₁₋₄alkyl, which is unsubstituted or substituted with 1-3        halo,    -   (8) —CN,    -   (9) —CO₂R⁹,    -   (10) —NR¹⁰R¹¹,    -   (11) —CONR^(10a)R^(11a), and    -   (12) —(NR^(10a))CO₂R⁹.

In an embodiment of the present invention R⁴ and R⁵ are independentlyselected from:

-   -   (1) hydrogen;    -   (2) —C₁₋₄alkyl, which is unsubstituted or substituted with 1-3        substituents each independently selected from:        -   (a) halo,        -   (b) hydroxy,        -   (c) —O—C₁₋₆alkyl,        -   (d) —C₃₋₆cycloallyl, and        -   (e) phenyl,    -   (3) —C₃₋₆cycloalkyl,    -   (4) phenyl, which is unsubstituted or substituted with 1-3        substituents each independently selected from:        -   (a) —C₁₋₄alkyl, which is unsubstituted or substituted with            1-3 fluoro, and        -   (b) halo,    -   (5) halo,    -   (6) hydroxy,    -   (7) —O—C₁₋₆alkyl, which is unsubstituted or substituted with 1-3        fluoro,    -   (8) —CN, and    -   (9) —NR¹⁰R¹¹;

In an embodiment of the present invention R⁴ and R⁵ are independentlyselected from:

-   -   (1) hydrogen;    -   (2) —C₁₋₄alkyl, which is unsubstituted or substituted with 1-3        fluoro,    -   (3) phenyl,    -   (5) halo, and    -   (6) hydroxy;

In an embodiment of the present invention R⁴ and R⁵ are independentlyselected from: hydrogen, halo, and methyl.

In an embodiment of the present invention R⁴ is hydrogen.

In an embodiment of the present invention R⁵ is hydrogen.

In an embodiment of the present invention R⁶ is selected from:

-   -   (1) hydrogen,    -   (2) —C₁₋₄alkyl which is unsubstituted or substituted with 1-5        substituents each independently selected from:        -   (a) halo,        -   (b) hydroxy,        -   (c) —C₃₋₆cycloalkyl, and        -   (d) phenyl,    -   (3) phenyl or heterocycle, wherein heterocycle is selected from:        pyridinyl, pyrimidinyl, or pyrazinyl,

In an embodiment of the present invention R⁶ is selected from:

-   -   (1) hydrogen,    -   (2) —C₁₋₄alkyl which is unsubstituted or substituted with 1-3        substituents each independently selected from:        -   (a) halo, and        -   (b) phenyl.

In an embodiment of the present invention R⁶ is hydrogen or methyl.

In an embodiment of the present invention R⁶ is methyl.

In an embodiment of the present invention R⁹ is selected from:

-   -   (i) hydrogen,    -   (ii) —C₁₋₆alkyl, which is unsubstituted or substituted with 1-3        substituents, substituents each independently selected from:        -   (I) halo,        -   (II) hydroxy,            -   (III) —O—C₁₋₄alkyl,            -   (IV) —C₃₋₆cycloalkyl,            -   (V) phenyl, which is unsubstituted or substituted with                1-3 substituents each independently selected from:                -   (1) —C₁₋₄alkyl,                -   (2) —O—C₁₋₄alkyl, and                -   (3) halo,            -   (iii) —C₃₋₆cycloalkyl, and            -   (iv) phenyl or heterocycle, wherein heterocycle is                selected from: pyridinyl, pyrimidinyl, pyrazinyl,                thienyl, pyrrolidinyl, thiazolyl, oxazolyl, imidazolyl,                triazolyl, tetrazolyl, imidazolinyl, indolinyl, indolyl,                quinolinyl, isoquinolinyl, piperidinyl, piperazinyl, and                morpholinyl, which phenyl or heterocycle is                unsubstituted or substituted with 1-3 substituents each                independently selected from:    -   (I) halo,    -   (II) —C₁₋₄alkyl,    -   (III) —O—C₁₋₄alkyl, and    -   (IV) oxo.

In an embodiment of the present invention R⁹ is selected from:

-   -   (i) hydrogen,    -   (ii) —C₁₋₄alkyl, which is unsubstituted or substituted with 1-3        substituents, substituents each independently selected from:        -   (I) halo, and        -   (II) hydroxy,    -   (iii) —C₃₋₆cycloalkyl, and    -   (iv) phenyl.

In an embodiment of the present invention R¹⁰ and R¹¹ are eachindependently selected from:

-   -   (i) hydrogen,    -   (ii) —C₁₋₆alkyl, which is unsubstituted or substituted with 1-3        substituents each independently selected from:        -   (I) —O—C₁₋₄alkyl,        -   (II) halo,        -   (III) hydroxy,        -   (IV) —C₃₋₆cycloalkyl, and        -   (V) phenyl,    -   (iii) —C₄₋₆cycloalkyl,    -   (iv) phenyl, which is unsubstituted or substituted with 1-3        substituents where the substituents are independently selected        from:        -   (I) —C₁₋₄alkyl,        -   (II) —O—C₁₋₄alkyl, and        -   (III) halo,    -   (v) benzyl, which is unsubstituted or substituted with 1-3        substituents where the substituents are independently selected        from:        -   (I) —C₁₋₄alkyl,        -   (II) —O—C₁₋₄alkyl, and        -   (III) halo,    -   (vi) —COR⁹, and    -   (vii) —SO₂R¹².

In an embodiment of the present invention R¹⁰ and R¹¹ are eachindependently selected from:

-   -   (i) hydrogen,    -   (ii) —C₁₋₄alkyl, which is unsubstituted or substituted with 1-3        substituents each independently selected from:        -   (I) —O—C₁₋₄alkyl, and        -   (II) halo,    -   (iii) —C₄₋₆cycloalkyl,    -   (iv) phenyl,    -   (v) benzyl,    -   (vi) —COR⁹, and    -   (vii) —SO₂R¹².

In an embodiment of the present invention R^(10a) and R^(11a) are eachindependently selected from:

-   -   (i) hydrogen,    -   (ii) —C₁₋₄alkyl, which is unsubstituted or substituted with 1-3        substituents each independently selected from:        -   (I) —O—C₁₋₄alkyl,        -   (II) halo,        -   (III) hydroxy,        -   (IV) —C₃₋₆cycloalkyl, and        -   (V) phenyl,    -   (iii) —C₅₋₆cycloalkyl,    -   (iv) phenyl, which is unsubstituted or substituted with 1-3        substituents where the substituents are independently selected        from:        -   (I) —C₁₋₄alkyl,        -   (II) —O—C₁₋₄alkyl,        -   (III) halo,        -   (IV) hydroxy, and        -   (V) trifluoromethyl,    -   (v) benzyl, which is unsubstituted or substituted with 1-3        substituents where the substituents are independently selected        from:        -   (I) —C₁₋₄alkyl,        -   (II) —O—C₁₋₄alkyl,        -   (III) halo, and        -   (IV) trifluoromethyl,    -   or where R^(10a) and R^(11a) join to form a ring selected from        azetidinyl, pyrrolidinyl, piperidinyl, azepanyl, piperazinyl, or        morpholinyl, which ring is unsubstituted or substituted with 1-5        substituents each independently selected from:    -   (I) —C₁₋₄alkyl, which is unsubstituted or substituted with 1-3        fluoro,    -   (II) —O—C₁₋₄alkyl, which is unsubstituted or substituted with        1-3 fluoro,    -   (III) halo,    -   (IV) hydroxy,    -   (V) phenyl, and    -   (VII) —COR⁹.

In an embodiment of the present invention R^(10a) and R^(11a) are eachindependently selected from:

-   -   (i) hydrogen,    -   (ii) —C₁₋₄alkyl, which is unsubstituted or substituted with 1-3        halo,    -   (iii) —C₅₋₆cycloalkyl,    -   (iv) phenyl, and    -   (v) benzyl,    -   or where R^(10a) and R^(11a) join to form a ring selected from        pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl, which        ring is unsubstituted or substituted with 1-3 substituents each        independently selected from:        -   (I) —C₁₋₄alkyl,        -   (II) halo, and        -   (III) hydroxy.

In an embodiment of the present invention R¹² is selected from:

-   -   (i) —C₁₋₆alkyl, which is unsubstituted or substituted with 1-3        fluoro,    -   (ii) —C₃₋₆cycloallyl,    -   (iii) phenyl or heterocycle, wherein heterocycle is selected        from: pyridinyl, pyrimidinyl, pyrazinyl, piperidinyl,        piperazinyl, pyrrolidinyl, thienyl, or morpholinyl,        -   which phenyl or heterocycle is unsubstituted or substituted            with 1-3 substituents independently selected from:        -   (I) —C₁₋₄alkyl,        -   (II) —O—C₁₋₄alkyl, and        -   (III) halo,    -   (iv) benzyl, which is unsubstituted or substituted with 1-3        substituents independently selected from:        -   (I) —C₁₋₄alkyl, and        -   (II) halo.

In an embodiment of the present invention R¹² is selected from:

-   -   (i) —C₁₋₄alkyl,    -   (ii) —C₃₋₆cycloalkyl,    -   (iii) phenyl, and    -   (iv) benzyl.

It is to be understood that where one or more of the above recitedstructures or substructures recite multiple substituents having the samedesignation each such variable may be the same or different from eachsimilarly designated variable. For example, R² is recited four times informula I, and each R² in formula I may independently be any of thesubstructures defined under R². The invention is not limited tostructures and substructures wherein each R² must be the same for agiven structure. The same is true with respect to any variable appearingmultiple times in a structure or substructure.

The compounds of the present invention may contain one or moreasymmetric centers and can thus occur as racemates and racemic mixtures,single enantiomers, diastereomeric mixtures and individualdiastereomers. Additional asymmetric centers may be present dependingupon the nature of the various substituents on the molecule. Each suchasymmetric center will independently produce two optical isomers and itis intended that all of the possible optical isomers and diastereomersin mixtures and as pure or partially purified compounds are includedwithin the ambit of this invention. The present invention is meant tocomprehend all such isomeric forms of these compounds.

Some of the compounds described herein contain olefinic double bonds,and unless specified otherwise, are meant to include both E and Zgeometric isomers.

The independent syntheses of these diastereomers or theirchromatographic separations may be achieved as known in the art byappropriate modification of the methodology disclosed herein. Theirabsolute stereochemistry may be determined by the x-ray crystallographyof crystalline products or crystalline intermediates which arederivatized, if necessary, with a reagent containing an asymmetriccenter of known absolute configuration.

If desired, racemic mixtures of the compounds may be separated so thatthe individual enantiomers are isolated. The separation can be carriedout by methods well known in the art, such as the coupling of a racemicmixture of compounds to an enantiomerically pure compound to form adiastereomeric mixture, followed by separation of the individualdiastereomers by standard methods, such as fractional crystallization orchromatography. The coupling reaction is often the formation of saltsusing an enantiomerically pure acid or base. The diasteromericderivatives may then be converted to the pure enantiomers by cleavage ofthe added chiral residue. The racemic mixture of the compounds can alsobe separated directly by chromatographic methods utilizing chiralstationary phases, which methods are well known in the art.

Alternatively, any enantiomer of a compound may be obtained bystereoselective synthesis using optically pure starting materials orreagents of known configuration by methods well known in the art.

As will be appreciated by those of skill in the art, not all of the R¹⁰and R¹¹ substituents are capable of forming a ring structure. Moreover,even those substituents capable of ring formation may or may not form aring structure.

Also as appreciated by those of skill in the art, halo or halogen asused herein are intended to include chloro, fluoro, bromo and iodo.

As used herein, “alkyl” is intended to mean linear, branched and cyclicstructures having no double or triple bonds. Thus C₁₋₆alkyl is definedto identify the group as having 1, 2, 3, 4, 5 or 6 carbons in a linearor branched arrangement, such that C₁₋₆alkyl specifically includesmethyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, tert-butyl,pentyl and hexyl. “Cycloalkyl” is an alkyl, part or all of which forms aring of three or more atoms. C₀ or C₀alkyl is defined to identify thepresence of a direct covalent bond.

The term “alkenyl” means linear or branched structures and combinationsthereof, of the indicated number of carbon atoms, having at least onecarbon-to-carbon double bond, wherein hydrogen may be replaced by anadditional carbon-to-carbon double bond. C₂₋₆alkenyl, for example,includes ethenyl, propenyl, 1-methylethenyl, butenyl and the like.

The term “alkynyl” means linear or branched structures and combinationsthereof, of the indicated number of carbon atoms, having at least onecarbon-to-carbon triple bond. Thus C₂₋₆alkynyl is defined to identifythe group as having 2, 3, 4, 5 or 6 carbons in a linear or branchedarrangement, such that C₂₋₆alkynyl specifically includes 2-hexynyl and2-pentynyl.

As used herein, “aryl” is intended to mean any stable monocyclic orbicyclic carbon ring of up to 7 members in each ring, wherein at leastone ring is aromatic. Examples of such aryl elements include phenyl,napthyl, tetrahydronapthyl, indanyl, or biphenyl.

The term “heterocycle” or “heterocyclic”, as used herein except wherenoted, represents a stable 4- to 7-membered monocyclic- or stable 8- to11-membered bicyclic heterocyclic ring system which is either saturatedor unsaturated, and which consists of carbon atoms and from one to fourheteroatoms selected from the group consisting of N, O and S, andwherein the nitrogen and sulfur heteroatoms may optionally be oxidized,and the nitrogen heteroatom may optionally be quaternized, and includingany bicyclic group in which any of the above-defined heterocyclic ringsis fused to a benzene ring. The heterocyclic ring may be attached at anyheteroatom or carbon atom which results in the creation of a stablestructure. Examples of such heterocyclic groups include, but are notlimited to, azetidine, chroman, dihydrofuran, dihydropyran, dioxane,dioxolane, hexahydroazepine, imidazolidine, imidazolidinone,imidazoline, imidazolinone, indoline, isochroman, isoindoline,isothiazoline, isothiazolidine, isoxazoline, isoxazolidine, morpholine,morpholinone, oxazoline, oxazolidine, oxazolidinone, oxetane,2-oxohexahydroazepin, 2-oxopiperazine, 2-oxopiperidine,2-oxopyrrolidine, piperazine, piperidine, pyran, pyrazolidine,pyrazoline, pyrrolidine, pyrroline, quinuclidine, tetrahydrofuran,tetrahydropyran, thiamorpholine, thiazoline, thiazolidine,thiomorpholine and N-oxides thereof.

The term “heteroaryl”, as used herein except where noted, represents astable 5- to 7-membered monocyclic- or stable 9- to 10-membered fusedbicyclic heterocyclic ring system which contains an aromatic ring, anyring of which may be saturated, such as piperidinyl, partiallysaturated, or unsaturated, such as pyridinyl, and which consists ofcarbon atoms and from one to four heteroatoms selected from the groupconsisting of N, O and S, and wherein the nitrogen and sulfurheteroatoms may optionally be oxidized, and the nitrogen heteroatom mayoptionally be quaternized, and including any bicyclic group in which anyof the above-defined heterocyclic rings is fused to a benzene ring. Theheterocyclic ring may be attached at any heteroatom or carbon atom whichresults in the creation of a stable structure. Examples of suchheteroaryl groups include, but are not limited to, benzimidazole,benzisothiazole, benzisoxazole, benzofuran, benzothiazole,benzothiophene, benzotriazole, benzoxazole, carboline, cinnoline, furan,furazan, imidazole, indazole, indole, indolizine, isoquinoline,isothiazole, isoxazole, naphthyridine, oxadiazole, oxazole, phthalazine,pteridine, purine, pyran, pyrazine, pyrazole, pyridazine, pyridine,pyrimidine, pyrrole, quinazoline, quinoline, quinoxaline, tetrazole,thiadiazole, thiazole, thiophene, triazine, triazole, and N-oxidesthereof.

The term “alkoxy,” as in C₁-C₆ alkoxy, is intended to refer to includealkoxy groups of from 1 to 6 carbon atoms of a straight, branched andcyclic configuration. Examples include methoxy, ethoxy, propoxy,isopropoxy, cyclopropyloxy, cyclohexyloxy and the like.

The phrase “pharmaceutically acceptable” is employed herein to refer tothose compounds, materials, compositions, and/or dosage forms which are,within the scope of sound medical judgment, suitable for use in contactwith the tissues of human beings and animals without excessive toxicity,irritation, allergic response, or other problem or complication,commensurate with a reasonable benefit/risk ratio.

As used herein, “pharmaceutically acceptable salts” refer to derivativeswherein the parent compound is modified by making acid or base saltsthereof. Examples of pharmaceutically acceptable salts include, but arenot limited to, mineral or organic acid salts of basic residues such asamines; alkali or organic salts of acidic residues such as carboxylicacids; and the like. The pharmaceutically acceptable salts include theconventional non-toxic salts or the quaternary ammonium salts of theparent compound formed, for example, from non-toxic inorganic or organicacids. For example, such conventional non-toxic salts include thosederived from inorganic acids such as hydrochloric, hydrobromic,sulfuric, sulfamic, phosphoric, nitric and the like; and the saltsprepared from organic acids such as acetic, propionic, succinic,glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic,maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic,sulfanilic, 2-acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic,ethane disulfonic, oxalic, isethionic, and the like.

The terms “bond” and “absent” are in certain instances herein usedinterchangeably to refer to an atom (or chemical moiety) which is notpresent in a particular embodiment of the invention. In suchembodiments, the atoms adjacent the “bond” or “absent” atom are simplybonded to one another. For example, in certain embodiments of theinvention described and claimed herein, where -A¹-A²-A³-links B⁴ to E²,A¹ is defined as CR¹³R¹⁴ while A² and A³ are described as “absent”. Insuch a molecule, it is understood that A¹ is bonded directly to themoiety adjacent A³, i.e. the moiety E², resulting in the sub-structureB⁴-A¹-E². The absence of a specific atom or moiety, particularly an atomor moiety which serves to link or connect other atoms or moieties, doesnot imply that such other atoms or moieties are not linked.

When the compound of the present invention is basic, salts may beprepared from pharmaceutically acceptable non-toxic acids, includinginorganic and organic acids. Such acids include acetic, benzenesulfonic,benzoic, camphorsulfonic, citric, ethanesulfonic, fumaric, gluconic,glutamic, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic,mandelic, methanesulfonic, mucic, nitric, pamoic, pantothenic,phosphoric, succinic, sulfuric, tartaric, p-toluenesulfonic acid, andthe like. In one aspect of the invention the salts are citric,hydrobromic, hydrochloric, maleic, phosphoric, sulfuric, fumaric, andtartaric acids. It will be understood that, as used herein, referencesto the compounds of Formula I are meant to also include thepharmaceutically acceptable salts.

Exemplifying the invention is the use of the compounds disclosed in theExamples and herein. Specific compounds within the present inventioninclude a compound which selected from the group consisting of thecompounds disclosed in the following Examples and pharmaceuticallyacceptable salts thereof and individual diastereomers thereof.

The subject compounds are useful in a method of antagonism of CGRPreceptors in a patient such as a mammal in need of such antagonismcomprising the administration of an effective amount of the compound.The present invention is directed to the use of the compounds disclosedherein as antagonists of CGRP receptors. In addition to primates,especially humans, a variety of other mammals can be treated accordingto the method of the present invention.

Another embodiment of the present invention is directed to a method forthe treatment, control, amelioration, or reduction of risk of a diseaseor disorder in which the CGRP receptor is involved in a patient thatcomprises administering to the patient a therapeutically effectiveamount of a compound that is an antagonist of CGRP receptors.

The present invention is further directed to a method for themanufacture of a medicament for antagonism of CGRP receptors activity inhumans and animals comprising combining a compound of the presentinvention with a pharmaceutical carrier or diluent.

The subject treated in the present methods is generally a mammal, forexample a human being, male or female, in whom antagonism of CGRPreceptor activity is desired. The term “therapeutically effectiveamount” means the amount of the subject compound that will elicit thebiological or medical response of a tissue, system, animal or human thatis being sought by the researcher, veterinarian, medical doctor or otherclinician. As used herein, the term “treatment” refers both to thetreatment and to the prevention or prophylactic therapy of the mentionedconditions, particularly in a patient who is predisposed to such diseaseor disorder.

The term “composition” as used herein is intended to encompass a productcomprising the specified ingredients in the specified amounts, as wellas any product which results, directly or indirectly, from combinationof the specified ingredients in the specified amounts. Such term inrelation to pharmaceutical composition, is intended to encompass aproduct comprising the active ingredient(s), and the inert ingredient(s)that make up the carrier, as well as any product which results, directlyor indirectly, from combination, complexation or aggregation of any twoor more of the ingredients, or from dissociation of one or more of theingredients, or from other types of reactions or interactions of one ormore of the ingredients. Accordingly, the pharmaceutical compositions ofthe present invention encompass any composition made by admixing acompound of the present invention and a pharmaceutically acceptablecarrier. By “pharmaceutically acceptable” it is meant the carrier,diluent or excipient must be compatible with the other ingredients ofthe formulation and not deleterious to the recipient thereof.

The terms “administration of” and or “administering a” compound shouldbe understood to mean providing a compound of the invention or a prodrugof a compound of the invention to the individual in need of treatment.

The utility of the compounds in accordance with the present invention asantagonists of CGRP receptor activity may be demonstrated by methodologyknown in the art. Inhibition of the binding of ¹²⁵I-CGRP to receptorsand functional antagonism of CGRP receptors were determined as follows:

NATIVE RECEPTOR BINDING ASSAY: The binding of ¹²⁵I-CGRP to receptors inSK-N-MC cell membranes was carried out essentially as described(Edvinsson et al. (2001) Eur. J. Pharmacol. 415, 39-44). Briefly,membranes (25 μg) were incubated in 1 ml of binding buffer [10 mM HEPES,pH 7.4, 5 mM MgCl₂ and 0.2% bovine serum albumin (BSA)] containing 10 pM¹²⁵I-CGRP and antagonist. After incubation at room temperature for 3 h,the assay was terminated by filtration through GFB glass fibre filterplates (Millipore) that had been blocked with 0.5% polyethyleneimine for3 h. The filters were washed three times with ice-cold assay buffer,then the plates were air dried. Scintillation fluid (50 μl) was addedand the radioactivity was counted on a Topcount (Packard Instrument).Data analysis was carried out by using Prism and the K_(i) wasdetermined by using the Cheng-Prusoff equation (Cheng & Prusoff (1973)Biochem. Pharmacol. 22, 3099-3108).

NATIVE RECEPTOR FUNCTIONAL ASSAY: SK-N-MC cells were grown in minimalessential medium (MEM) supplemented with 10% fetal bovine serum, 2 mML-glutamine, 0.1 mM non-essential amino acids, 1 mM sodium pyruvate, 100units/ml penicillin and 100 μg/ml streptomycin at 37° C., 95% humidity,and 5% CO₂. For cAMP assays, cells were plated at 5×10⁵ cells/well in96-well poly-D-lysine-coated plates (Becton-Dickinson) and cultured for˜18 h before assay. Cells were washed with phosphate-buffered saline(PBS, Sigma) then pre-incubated with 300 μM isobutylmethylxanthine inserum-free MEM for 30 min at 37° C. Antagonist was added and the cellswere incubated for 10 min before the addition of CGRP. The incubationwas continued for another 15 min, then the cells were washed with PBSand processed for cAMP determination according to the manufacturer'srecommended protocol. Maximal stimulation over basal was defined byusing 100 nM CGRP. Dose-response curves were generated by using Prism.Dose-ratios (DR) were calculated and used to construct full Schild plots(Arunlakshana & Schild (1959) Br. J. Pharmacol. 14, 48-58).

RECOMBINANT RECEPTOR: Human CRLR (Genbank accession number L76380) wassubcloned into the expression vector pIREShyg2 (BD Biosciences Clontech)as a 5′NheI and 3′ PmeI fragment. Human RAMP1 (Genbank accession numberAJ001014) was subcloned into the expression vector pIRESpuro2 (BDBiosciences Clontech) as a 5′NheI and 3′NotI fragment. 293 cells (humanembryonic kidney cells; ATCC #CRL-1573) were cultured in DMEM with 4.5g/L glucose, 1 mM sodium pyruvate and 2 mM glutamine supplemented with10% fetal bovine serum (FBS), 100 units/mL penicillin and 100 ug/mlstreptomycin, and maintained at 37° C. and 95% humidity. Cells weresubcultured by treatment with 0.25% trypsin with 0.1% EDTA in HBSS.Stable cell line generation was accomplished by co-transfecting 10 ug ofDNA with 30 ug Lipofectamine 2000 (Invitrogen) in 75 cm² flasks. CRLRand RAMP expression constructs were co-transfected in equal amounts.Twenty-four hours after transfection the cells were diluted andselective medium (growth medium+300 ug/ml hygromycin and 1 ug/mlpuromycin) was added the following day. A clonal cell line was generatedby single cell deposition utilizing a FACS Vantage SE (BectonDickinson). Growth medium was adjusted to 150 ug/ml hygromycin and 0.5ug/ml puromycin for cell propagation.

RECOMBINANT RECEPTOR BINDING ASSAY: Cells expressing recombinant humanCRLR/RAMP1 were washed with PBS and harvested in harvest buffercontaining 50 mM HEPES, 1 mM EDTA and Complete protease inhibitors(Roche). The cell suspension was disrupted with a laboratory homogenizerand centrifuged at 48,000 g to isolate membranes. The pellets wereresuspended in harvest buffer plus 250 mM sucrose and stored at −70° C.For binding assays, 10 ug of membranes were incubated in 1 ml bindingbuffer (10 mM HEPES, pH 7.4, 5 mM MgCl₂, and 0.2% BSA) for 3 hours atroom temperature containing 10 pM ¹²⁵I-hCGRP (Amersham Biosciences) andantagonist. The assay was terminated by filtration through 96-well GFBglass fiber filter plates (Millipore) that had been blocked with 0.05%polyethyleneimine. The filters were washed 3 times with ice-cold assaybuffer (10 mM HEPES, pH 7.4). Scintillation fluid was added and theplates were counted on a Topcount (Packard). Non-specific binding wasdetermined and the data analysis was carried out with the apparentdissociation constant (K_(i)) determined by using a non-linear leastsquares fitting the bound CPM data to the equation below:

$Y_{obsd} = \frac{\begin{matrix}{{\left( {Y_{\max} - Y_{\min}} \right)\left( {{\% \mspace{11mu} I_{\max}} - {\% \mspace{11mu} {I_{\min}/100}}} \right)} +} \\{Y_{\min} + {\left( {Y_{\max} - Y_{\min}} \right)\left( {100 - {\% \mspace{11mu} {I_{\max}/100}}} \right)}}\end{matrix}}{1 + \left( {\lbrack{Drug}\rbrack/{K_{i}\left( {1 + {\lbrack{Radiolabel}\rbrack/K_{d}}} \right)}^{nH}} \right.}$

Where Y is observed CPM bound, Y_(max) is total bound counts, Y min isnon specific bound counts, (Y max−Y min) is specific bound counts, % 1max is the maximum percent inhibition, % 1 min is the minimum percentinhibition, radiolabel is the probe, and the K_(d) is the apparentdissociation constant for the radioligand for the receptor as determinedby Hot saturation experiments.

RECOMBINANT RECEPTOR FUNCTIONAL ASSAY: Cells were plated in completegrowth medium at 85,000 cells/well in 96-well poly-D-lysine coatedplates (Corning) and cultured for ˜19 h before assay. Cells were washedwith PBS and then incubated with inhibitor for 30 min at 37° C. and 95%humidity in Cellgro Complete Serum-Free/Low-Protein medium (Mediatech,Inc.) with L-glutamine and 1 g/L BSA. Isobutyl-methylxanthine was addedto the cells at a concentration of 300 μM and incubated for 30 min at37° C. Human α-CGRP was added to the cells at a concentration of 0.3 nMand allowed to incubate at 37° C. for 5 min. After (X-CGRP stimulationthe cells were washed with PBS and processed for cAMP determinationutilizing the two-stage assay procedure according to the manufacturer'srecommended protocol (cAMP SPA direct screening assay system; RPA 559;Amersham Biosciences). Dose response curves were plotted and IC₅₀ valuesdetermined from a 4-parameter logistic fit as defined by the equationy=((a−d)/(1+(x/c)^(b))+d, where y=response, x=dose, a=max response,d=min response, c=inflection point and b=slope.

In particular, the compounds of the following examples had activity asantagonists of the CGRP receptor in the aforementioned assays, generallywith a K; or IC₅₀ value of less than about 50 μM. Such a result isindicative of the intrinsic activity of the compounds in use asantagonists of CGRP receptors.

The ability of the compounds of the present invention to act as CGRPantagonists makes them useful pharmacological agents for disorders thatinvolve CORP in humans and animals, but particularly in humans.

The compounds of the present invention have utility in treating,preventing, ameliorating, controlling or reducing the risk of one ormore of the following conditions or diseases: headache; migraine;cluster headache; chronic tension type headache; pain; chronic pain;neurogenic inflammation and inflammatory pain; neuropathic pain; eyepain; tooth pain; diabetes; non-insulin dependent diabetes mellitus;vascular disorders; inflammation; arthritis; bronchial hyperreactivity,asthma; shock; sepsis; opiate withdrawal syndrome; morphine tolerance;hot flashes in men and women; allergic dermatitis; psoriasis;encephalitis; brain trauma; epilepsy; neurodegenerative diseases; skindiseases; neurogenic cutaneous redness, skin rosaceousness and erythema;inflammatory bowel disease, irritable bowel syndrome, cystitis; andother conditions that may be treated or prevented by antagonism of CGRPreceptors. Of particular importance is the acute or prophylactictreatment of headache, including migraine and cluster headache.

The subject compounds are further useful in a method for the prevention,treatment, control, amelioration, or reduction of risk of the diseases,disorders and conditions noted herein.

The subject compounds are further useful in a method for the prevention,treatment, control, amelioration, or reduction of risk of theaforementioned diseases, disorders and conditions in combination withother agents.

The compounds of the present invention may be used in combination withone or more other drugs in the treatment, prevention, control,amelioration, or reduction of risk of diseases or conditions for whichcompounds of Formula I or the other drugs may have utility, where thecombination of the drugs together are safer or more effective thaneither drug alone. Such other drug(s) may be administered, by a routeand in an amount commonly used therefor, contemporaneously orsequentially with a compound of Formula I. When a compound of Formula Iis used contemporaneously with one or more other drugs, a pharmaceuticalcomposition in unit dosage form containing such other drugs and thecompound of Formula I is preferred. However, the combination therapy mayalso include therapies in which the compound of Formula I and one ormore other drugs are administered on different overlapping schedules. Itis also contemplated that when used in combination with one or moreother active ingredients, the compounds of the present invention and theother active ingredients may be used in lower doses than when each isused singly. Accordingly, the pharmaceutical compositions of the presentinvention include those that contain one or more other activeingredients, in addition to a compound of Formula I.

For example, the present compounds may be used in conjunction with ananti-migraine agent, such as ergotamine and dihydroergotamine, or otherserotonin agonists, especially a 5-HT_(1B/1D) agonist, for examplesumatriptan, naratriptan, zolmitriptan, eletriptan, almotriptan,frovatriptan, donitriptan, and rizatriptan, a 5-HT_(1D) agonist such asPNU-142633 and a 5-HT_(1F) agonist such as LY334370; a cyclooxygenaseinhibitor, such as a selective cyclooxygenase-2 inhibitor, for examplerofecoxib, etoricoxib, celecoxib, valdecoxib or paracoxib; anon-steroidal anti-inflammatory agent or a cytokine-suppressinganti-inflammatory agent, for example with a compound such as ibuprofen,ketoprofen, fenoprofen, naproxen, indomethacin, sulindac, meloxicam,piroxicam, tenoxicam, lomoxicam, ketorolac, etodolac, mefenamic acid,meclofenamic acid, flufenarmic acid, tolfenamic acid, diclofenac,oxaprozin, apazone, nimesulide, nabumetone, tenidap, etanercept,tolmetin, phenylbutazone, oxyphenbutazone, diflunisal, salsalate,olsalazine or sulfasalazine and the like; or glucocorticoids. Similarly,the instant compounds may be administered with an analgesic such asaspirin, acetaminophen, phenacetin, fentanyl, sufentanil, methadone,acetyl methadol, buprenorphine or morphine.

Additionally, the present compounds may be used in conjunction with aninterleukin inhibitor, such as an interleukin-1 inhibitor; an NK-1receptor antagonist, for example aprepitant; an NMDA antagonist; an NR2Bantagonist; a bradykinin-1 receptor antagonist; an adenosine A1 receptoragonist; a sodium channel blocker, for example lamotrigine; an opiateagonist such as levomethadyl acetate or methadyl acetate; a lipoxygenaseinhibitor, such as an inhibitor of 5-lipoxygenase; an alpha receptorantagonist, for example indoramin; an alpha receptor agonist; avanilloid receptor antagonist; a renin inhibitor; a granzyme Binhibitor; a substance P antagonist; an endothelin antagonist; anorepinephrin precursor; anti-anxiety agents such as diazepam,alprazolam, chlordiazepoxide and chlorazepate; serotonin 5HT₂ receptorantagonists; opiod agonists such as codeine, hydrocodone, tramadol,dextropropoxyphene and febtanyl; an mGluR5 agonist, antagonist orpotentiator; a GABA A receptor modulator, for example acamprosatecalcium; nicotinic antagonists or agonists including nicotine;muscarinic agonists or antagonists; a selective serotonin reuptakeinhibitor, for example fluoxetine, paroxetine, sertraline, duloxetine,escitalopram, or citalopram; an antidepressant, for exampleamitriptyline, nortriptyline, clomipramine, imipramine, venlafaxine,doxepin, protriptyline, desipramine, trimipramine, or imipramine; aleukotriene antagonist, for example montelukast or zafirlukast; aninhibitor of nitric oxide or an inhibitor of the synthesis of nitricoxide.

Also, the present compounds may be used in conjunction with gap junctioninhibitors; neuronal calcium channel blockers such as civamide; AMPA/KAantagonists such as LY293558; sigma receptor agonists; and vitamin B2.

Also, the present compounds may be used in conjunction with ergotalkaloids other than ergotamine and dihydroergotamine, for exampleergonovine, ergonovine, methylergonovine, metergoline, ergoloidmesylates, dihydroergocornine, dihydroergocristine, dihydroergocryptine,dihydro-α-ergocryptine, dihydro-β-ergocryptine, ergotoxine, ergocornine,ergocristine, ergocryptine, α-ergocryptine, β-ergocryptine, ergosine,ergostane, bromocriptine, or methysergide.

Additionally, the present compounds may be used in conjunction with abeta-adrenergic antagonist such as timolol, propanolol, atenolol,metoprolol or nadolol, and the like; a MAO inhibitor, for examplephenelzine; a calcium channel blocker, for example flunarizine,diltiazem, amlodipine, felodipine, nisolipine, isradipine, nimodipine,lomerizine, verapamil, nifedipine, or prochlorperazine; neurolepticssuch as olanzapine, droperidol, prochlorperazine, chlorpromazine andquetiapine; an anticonvulsant such as topiramate, zonisamide,tonabersat, carabersat, levetiracetam, lamotrigine, tiagabine,gabapentin, pregabalin or divalproex sodium; an anti-hypertensive suchas an angiotensin U antagonist, for example losartan, irbesartin,valsartan, eprosartan, telmisartan, olmesartan, medoxomil, candesartanand candesartan cilexetil, an angiotensin I antagonist, an angiotensinconverting enzyme inhibitor such as lisinopril, enalapril, captopril,benazepril, quinapril, perindopril, ramipril and trandolapril; orbotulinum toxin type A or B.

The present compounds may be used in conjunction with a potentiator suchas caffeine, an H2-antagonist, simethicone, aluminum or magnesiumhydroxide; a decongestant such as oxymetazoline, epinephrine,naphazoline, xylometazoline, propylhexedrine, or levo-desoxy-ephedrine;an antitussive such as caramiphen, carbetapentane, or dextromethorphan;a diuretic; a prokinetic agent such as metoclopramide or domperidone; asedating or non-sedating antihistamine such as acrivastine, azatadine,bromodiphenhydramine, brompheniramine, carbinoxamine, chlorpheniramine,clemastine, dexbrompheniramine, dexchlorpheniramine, diphenhydramine,doxylamine, loratadine, phenindamine, pheniramine, phenyltoloxamine,promethazine, pyrilamine, terfenadine, triprolidine, phenylephrine,phenylpropanolamine, or pseudoephedrine. The present compounds also maybe used in conjunction with anti-emetics.

In a particularly preferred embodiment the present compounds are used inconjunction with an anti-migraine agent, such as: ergotamine ordihydroergotamine; a 5-HT₁ agonist, especially a 5-HT_(1B/1D) agonist,in particular, sumatriptan, naratriptan, zolmitriptan, eletriptan,almotriptan, frovatriptan, donitriptan, avitriptan and rizatriptan, andother serotonin agonists; and a cyclooxygenase inhibitor, such as aselective cyclooxygenase-2 inhibitor, in particular, rofecoxib,etoricoxib, celecoxib, valdecoxib or paracoxib.

The above combinations include combinations of a compound of the presentinvention not only with one other active compound, but also with two ormore other active compounds. Likewise, compounds of the presentinvention may be used in combination with other drugs that are used inthe prevention, treatment, control, amelioration, or reduction of riskof the diseases or conditions for which compounds of the presentinvention are useful. Such other drugs may be administered, by a routeand in an amount commonly used therefore, contemporaneously orsequentially with a compound of the present invention. When a compoundof the present invention is used contemporaneously with one or moreother drugs, a pharmaceutical composition containing such other drugs inaddition to the compound of the present invention is preferred.Accordingly, the pharmaceutical compositions of the present inventioninclude those that also contain one or more other active ingredients, inaddition to a compound of the present invention.

The weight ratio of the compound of the present invention to the otheractive ingredient(s) may be varied and will depend upon the effectivedose of each ingredient. Generally, an effective dose of each will beused. Thus, for example, when a compound of the present invention iscombined with another agent, the weight ratio of the compound of thepresent invention to the other agent will generally range from about1000:1 to about 1:1000, or from about 200:1 to about 1:200. Combinationsof a compound of the present invention and other active ingredients willgenerally also be within the aforementioned range, but in each case, aneffective dose of each active ingredient should be used.

In such combinations the compound of the present invention and otheractive agents may be administered separately or in conjunction. Inaddition, the administration of one element may be prior to, concurrentto, or subsequent to the administration of other agent(s), and via thesame or different routes of administration.

The compounds of the present invention may be administered by oral,parenteral (e.g., intramuscular, intraperitoneal, intravenous, ICV,intracisternal injection or infusion, subcutaneous injection, orimplant), by inhalation spray, nasal, vaginal, rectal, sublingual, ortopical routes of administration and may be formulated, alone ortogether, in suitable dosage unit formulations containing conventionalnon-toxic pharmaceutically acceptable carriers, adjuvants and vehiclesappropriate for each route of administration. In addition to thetreatment of warm-blooded animals the compounds of the invention areeffective for use in humans.

The pharmaceutical compositions for the administration of the compoundsof this invention may conveniently be presented in dosage unit form andmay be prepared by any of the methods well known in the art of pharmacy.All methods include the step of bringing the active ingredient intoassociation with the carrier which constitutes one or more accessoryingredients. In general, the pharmaceutical compositions are prepared byuniformly and intimately bringing the active ingredient into associationwith a liquid carrier or a finely divided solid carrier or both, andthen, if necessary, shaping the product into the desired formulation. Inthe pharmaceutical composition the active compound is included in anamount sufficient to produce the desired effect upon the process orcondition of diseases. As used herein, the term “composition” isintended to encompass a product comprising the specified ingredients inthe specified amounts, as well as any product which results, directly orindirectly, from combination of the specified ingredients in thespecified amounts.

The pharmaceutical compositions containing the active ingredient may bein a form suitable for oral use, for example, as tablets, troches,lozenges, aqueous or oily suspensions, dispersible powders or granules,emulsions, solutions, hard or soft capsules, or syrups or elixirs.Compositions intended for oral use may be prepared according to anymethod known to the art for the manufacture of pharmaceuticalcompositions and such compositions may contain one or more agentsselected from the group consisting of sweetening agents, flavoringagents, coloring agents and preserving agents in order to providepharmaceutically elegant and palatable preparations. Tablets contain theactive ingredient in admixture with non-toxic pharmaceuticallyacceptable excipients which are suitable for the manufacture of tablets.These excipients may be for example, inert diluents, such as calciumcarbonate, sodium carbonate, lactose, calcium phosphate or sodiumphosphate; granulating and disintegrating agents, for example, cornstarch, or alginic acid; binding agents, for example starch, gelatin oracacia; and lubricating agents, for example magnesium stearate, stearicacid or talc. The tablets may be uncoated or they may be coated by knowntechniques to delay disintegration and absorption in thegastrointestinal tract and thereby provide a sustained action over alonger period. For example, a time delay material such as glycerylmonostearate or glyceryl distearate may be employed. They may also becoated by the techniques described in the U.S. Pat. Nos. 4,256,108;4,166,452; and 4,265,874 to form osmotic therapeutic tablets for controlrelease. Oral tablets may also be formulated for immediate release, suchas fast melt tablets or wafers, rapid dissolve tablets or fast dissolvefilms.

Formulations for oral use may also be presented as hard gelatin capsuleswherein the active ingredient is mixed with an inert solid diluent, forexample, calcium carbonate, calcium phosphate or kaolin, or as softgelatin capsules wherein the active ingredient is mixed with water or anoil medium, for example peanut oil, liquid paraffin, or olive oil.

Aqueous suspensions contain the active materials in admixture withexcipients suitable for the manufacture of aqueous suspensions. Suchexcipients are suspending agents, for example sodiumcarboxymethylcellulose, methylcellulose, hydroxy-propylmethylcellulose,sodium alginate, polyvinyl-pyrrolidone, gum tragacanth and gum acacia;dispersing or wetting agents may be a naturally-occurring phosphatide,for example lecithin, or condensation products of an alkylene oxide withfatty acids, for example polyoxyethylene stearate, or condensationproducts of ethylene oxide with long chain aliphatic alcohols, forexample heptadecaethyleneoxycetanol, or condensation products ofethylene oxide with partial esters derived from fatty acids and ahexitol such as polyoxyethylene sorbitol monooleate, or condensationproducts of ethylene oxide with partial esters derived from fatty acidsand hexitol anhydrides, for example polyethylene sorbitan monooleate.The aqueous suspensions may also contain one or more preservatives, forexample ethyl, or n-propyl, p-hydroxybenzoate, one or more coloringagents, one or more flavoring agents, and one or more sweetening agents,such as sucrose or saccharin.

Oily suspensions may be formulated by suspending the active ingredientin a vegetable oil, for example arachis oil, olive oil, sesame oil orcoconut oil, or in a mineral oil such as liquid paraffin. The oilysuspensions may contain a thickening agent, for example beeswax, hardparaffin or cetyl alcohol. Sweetening agents such as those set forthabove, and flavoring agents may be added to provide a palatable oralpreparation. These compositions may be preserved by the addition of ananti-oxidant such as ascorbic acid.

Dispersible powders and granules suitable for preparation of an aqueoussuspension by the addition of water provide the active ingredient inadmixture with a dispersing or wetting agent, suspending agent and oneor more preservatives. Suitable dispersing or wetting agents andsuspending agents are exemplified by those already mentioned above.Additional excipients, for example sweetening, flavoring and coloringagents, may also be present.

The pharmaceutical compositions of the invention may also be in the formof oil-in-water emulsions. The oily phase may be a vegetable oil, forexample olive oil or arachis oil, or a mineral oil, for example liquidparaffin or mixtures of these. Suitable emulsifying agents may benaturally-occurring gums, for example gum acacia or gum tragacanth,naturally-occurring phosphatides, for example soy bean, lecithin, andesters or partial esters derived from fatty acids and hexitolanhydrides, for example sorbitan monooleate, and condensation productsof the said partial esters with ethylene oxide, for examplepolyoxyethylene sorbitan monooleate. The emulsions may also containsweetening and flavoring agents.

Syrups and elixirs may be formulated with sweetening agents, for exampleglycerol, propylene glycol, sorbitol or sucrose. Such formulations mayalso contain a demulcent, a preservative and flavoring and coloringagents.

The pharmaceutical compositions may be in the form of a sterileinjectable aqueous or oleagenous suspension. This suspension may beformulated according to the known art using those suitable dispersing orwetting agents and suspending agents which have been mentioned above.The sterile injectable preparation may also be a sterile injectablesolution or suspension in a non-toxic parenterally-acceptable diluent orsolvent, for example as a solution in 1,3-butane diol. Among theacceptable vehicles and solvents that may be employed are water,Ringer's solution and isotonic sodium chloride solution. In addition,sterile, fixed oils are conventionally employed as a solvent orsuspending medium. For this purpose any bland fixed oil may be employedincluding synthetic mono- or diglycerides. In addition, fatty acids suchas oleic acid find use in the preparation of injectables.

The compounds of the present invention may also be administered in theform of suppositories for rectal administration of the drug. Thesecompositions can be prepared by mixing the drug with a suitablenon-irritating excipient which is solid at ordinary temperatures butliquid at the rectal temperature and will therefore melt in the rectumto release the drug. Such materials are cocoa butter and polyethyleneglycols.

For topical use, creams, ointments, jellies, solutions or suspensions,etc., containing the compounds of the present invention are employed.Similarly, transdermal patches may also be used for topicaladministration.

The pharmaceutical composition and method of the present invention mayfurther comprise other therapeutically active compounds as noted hereinwhich are usually applied in the treatment of the above mentionedpathological conditions.

In the treatment, prevention, control, amelioration, or reduction ofrisk of conditions which require antagonism of CGRP receptor activity anappropriate dosage level will generally be about 0.01 to 500 mg per kgpatient body weight per day which can be administered in single ormultiple doses. A suitable dosage level may be about 0.01 to 250 mg/kgper day, about 0.05 to 100 mg/kg per day, or about 0.1 to 50 mg/kg perday. Within this range the dosage may be 0.05 to 0.5, 0.5 to 5 or 5 to50 mg/kg per day. For oral administration, the compositions may beprovided in the form of tablets containing 1.0 to 1000 milligrams of theactive ingredient, particularly 1.0, 5.0, 10.0, 15.0. 20.0, 25.0, 50.0,75.0, 100.0, 150.0, 200.0, 250.0, 300.0, 400.0, 500.0, 600.0, 750.0,800.0, 900.0, and 1000.0 milligrams of the active ingredient for thesymptomatic adjustment of the dosage to the patient to be treated. Thecompounds may be administered on a regimen of 1 to 4 times per day, ormay be administered once or twice per day.

When treating, preventing, controlling, ameliorating, or reducing therisk of headache, migraine, cluster headache, or other diseases forwhich compounds of the present invention are indicated, generallysatisfactory results are obtained when the compounds of the presentinvention are administered at a daily dosage of from about 0.1 milligramto about 100 milligram per kilogram of animal body weight, given as asingle daily dose or in divided doses two to six times a day, or insustained release form. For most large mammals, the total daily dosageis from about 1.0 milligrams to about 1000 milligrams, or from about 1milligrams to about 50 milligrams. In the case of a 70 kg adult human,the total daily dose will generally be from about 10 milligrams to about1000 milligrams. This dosage regimen may be adjusted to provide theoptimal therapeutic response.

It will be understood, however, that the specific dose level andfrequency of dosage for any particular patient may be varied and willdepend upon a variety of factors including the activity of the specificcompound employed, the metabolic stability and length of action of thatcompound, the age, body weight, general health, sex, diet, mode and timeof administration, rate of excretion, drug combination, the severity ofthe particular condition, and the host undergoing therapy.

Several methods for preparing the compounds of this invention areillustrated in the following schemes and examples. Starting materialsare made according to procedures known in the art or as illustratedherein.

The compounds of the present invention can be prepared readily accordingto the following schemes and specific examples, or modificationsthereof, using readily available starting materials, reagents andconventional synthesis procedures. In these reactions, it is alsopossible to make use of variants which are themselves known to those ofordinary skill in this art but are not mentioned in greater detail. Thegeneral procedures for making the compounds claimed in this inventioncan be readily understood and appreciated by one skilled in the art fromviewing the following schemes.

The synthesis of spirohydantoin intermediates may be conducted asdescribed in Schemes 1-9. Spirohydantoin intermediates bearing R⁴, R⁵,R¹³, R¹⁴ and R¹⁵ may be prepared by employing appropriately substitutedstarting materials or by derivatization of any intermediates and/orfinal products as desired by methods known in the art.

Commercially available 6-bromo-2-tetralone (1) may be readily convertedto the spirohydantoin 2 under Bucherer-Bergs conditions, using ammoniumcarbonate and either sodium cyanide or potassium cyanide. Other2-tetralones may be readily accessed using a variety of literaturemethods, such as the Friedel-Crafts reaction of arylacetyl chlorideswith ethene as described by Burckhalter and Campbell (J. Org. Chem.1961, 26, 4232) and converted to the corresponding spirohydantoinsanalogously. In Scheme 1, treatment of spirohydantoin 2 with ethylmagnesium bromide followed by tert-butyllithium effects metal-halogenexchange and the resulting aryllithium species is quenched with carbondioxide to give acid 3. A Schmidt reaction of 3 with hydrazoic acid maybe used to provide aniline 4, as reviewed by Wolff (Org. React. 1946, 3,307). Alternatively, a modified Curtius rearrangement using 3 anddiphenylphosphoryl azide according to the procedure of Yamada andcoworkers (Tetrahedron 1974, 30, 2151) can provide aniline 4 via eitherits tert-butyl or benzyl carbamate derivatives.

In Scheme 2, treatment of 6-bromo-2-tetralone (1) with methylaminehydrochloride and potassium cyanide, followed by potassium cyanate andhydrochloric acid, provides the methylated hydantoin derivative 5.Analogous procedures to those described in Scheme 1 may be used toprovide acid 6 and aniline 7.

Scheme 3 illustrates a route to 7-substituted tetralin derivatives 10and 11. 3-Bromophenylacetic acid is converted to the corresponding acidchloride and this is subjected to Friedel-Crafts reaction with ethene,affording the 7-bromo-2-tetralone 9. This intermediate may be elaboratedusing the procedures described in Scheme 1 to provide the acid (10) andaniline (11).

Scheme 4 details the synthesis of the key indane-based spirohydantoinintermediates. 2-Indanone (12) is converted to the spirohydantoin 13 viaBucherer-Bergs chemistry as shown. Treatment of 13 with nitric acidprovides the 5-nitroindane derivative 14, which may be reduced to thecorresponding aniline 15 under catalytic hydrogenation conditions.Alternatively, a two-step process can be employed to convert 2-indanone(12) into the N-methylspirohydantoin 16. Treatment of 12 with potassiumcyanide and methylamine hydrochloride affords an amino nitrile which isconverted to the spirohydantoin 16 using potassium cyanate and aceticacid. Subjection of 16 to the nitration-reduction sequence used for 13leads to the corresponding aniline 18, as detailed in Scheme 4.

Spirohydantoin intermediates may be resolved to give pure enantiomersusing techniques familiar to those skilled in the art. For example,chromatography of the nitro intermediate 17 on a ChiralPak AD column canbe used to provide the individual enantiomers (R)-17 and (S)-17, andthese enantiomers may be reduced to the corresponding anilines [(R)-18and (S)-18] by catalytic hydrogenation. Use of standard couplingprocedures using enantiomerically pure anilines affords the individualenantiomers of the final products. Resolution may be effected by othermethodologies, such as fractional crystallization of diastereomericsalts, and it may be carried out on other synthetic intermediates or onthe final products. Alternatively, an asymmetric synthesis of a keyintermediate, such as an amino acid precursor of a spirohydantoin, couldbe used to provide an enantiomerically enriched final product.

Spirohydantoin compounds containing R⁶ substituents other than hydrogenor methyl may be prepared by methods analogous to those for the caseswhere R⁶ is methyl in Scheme 2 and Scheme 4. Alternatively, a suitablyprotected spirohydantoin intermediate may be derivatized as shown inScheme 5.

The route illustrated in Scheme 5 uses a Mitsunobu reaction toselectively protect the imide nitrogen of spirohydantoin 14 with, forexample, X=4-methoxyphenyl. Other alkylation conditions may also beemployed in this protection step. The protected spirobydantoin 19 may bealkylated with a variety of R⁶ groups using sodium hydride or anotherbase to deprotonate the spirohydantoin. In the example shown, thebromide R⁶Br is utilized to effect the alkylation, but a variety ofother R⁶ derivatives, such as chlorides or sulfonates may be used. Otherconditions, such as copper or palladium promoted arylation orheteroarylation reactions may also be employed to install aryl orheteroaryl R⁶ groups. The spirohydantoin product 20 is then deprotectedto give 21. In Scheme 5, ammonium cerium (IV) nitrate is used to removethe 4-methoxybenzyl protecting group but the choice of deprotectionconditions may vary depending on the nature of X. Finally, hydrogenationconditions may be used to provide intermediate 22, in analogy with theprevious schemes.

Aniline intermediates, such as those described in Schemes 1-5, may beconverted to a variety of other key intermediates that are useful in thesynthesis of the compounds of the present invention. For example, Scheme6 illustrates methodology for conversion of a representative anilineinto several quinoline intermediates.

Aniline 22 may be acylated with (E)-3-ethoxyacryloyl chloride andtreatment of the resulting amide with sulfuric acid leads tohydroxyquinoline 29, which can be converted to the correspondingchloride 30 by heating in phosphorus oxychloride. Condensation ofaniline 22 with crotonaldehyde in the presence of acid and an oxidantaffords the 2-methylquinoline 31. The use of other aldehydes undersimilar conditions can lead to alternatively substituted quinolines.Oxidation of quinoline 31 with selenium dioxide can provide eitheraldehyde 32 or carboxylic acid 33, depending on the amount of oxidantused and the duration of the reaction. Reduction of aldehyde 32 withsodium borohydride provides the corresponding alcohol, and treatment ofthis with thionyl chloride may be used to give the chloride 34.Intermediates such as 30, 32, 33 and 34 may be converted to compounds ofthe present invention using a variety of known methodology. While themethodology shown in Scheme 6 is exemplified using aniline 22, it isunderstood that it may be applied to a variety of aniline substrates,such as those described herein, in order to provide various quinolineintermediates.

Scheme 7 illustrates the synthesis of a useful diamine intermediate. Theaniline 22 is converted to the trifluoroacetanilide, which is subjectedto standard nitration conditions, followed by removal of the acylprotecting group to give nitroaniline 35. Reduction of this nitrocompound, for example by catalytic hydrogenation, affords the phenylenediamine 36. The same nitroaniline intermediate (35) may be used toprovide other useful diamine intermediates. Another example is shown inScheme 8, in which 35 is elaborated to give the 2-aminophenethylamine42. Diazotization of the nitroaniline followed by reaction of thediazonium salt with potassium iodide affords 37, which may be protectedwith a 2-(trimethylsilyl)ethoxymethyl group. The resulting iodide 38 isa versatile intermediate which may be modified through a variety ofknown methodology. For example, palladium-mediated couplings can be usedto give many different products, such as the ester 39, which is obtainedwhen the coupling partner of the iodide is 2-tert-butoxy-2-oxoethylzincchloride, as shown in Scheme 8. Simultaneous removal of the tert-butylester and SEM protecting groups provides the acid 40. This acid may bereduced to the alcohol, and subsequent treatment with DPPA converts thealcohol to the corresponding azide 41. Catalytic hydrogenation, or anumber of other known methodologies, can be employed to reduce both thenitro and azido moieties to give the corresponding diamine 42.

The methodology illustrated in the foregoing Schemes 6-8 describes thesynthesis of some intermediates that are useful for making the compoundsof the present invention. While the examples shown involve analogues ofaniline 22, those skilled in the art will appreciate that suchmethodology may be extended to a variety of other anilines to give otheruseful intermediates. For example, Scheme 9 illustrates the synthesis ofheterocyclic intermediates that are analogous to those in Scheme 6 butof a more general structure.

It is understood by those skilled in the art that in some casesalternative reagents or conditions may be used to effect thetransformations in Scheme 9. In some cases, additional chemical stepsmay be required to obtain the compounds of interest, or variousprotecting group strategies may be employed.

The intermediates described in Schemes 6-9 may be used to synthesize thecompounds of the present invention using a variety of knownmethodologies. Some of these methodologies are illustrated in Scheme 10.Standard reductive amination of an aldehyde like 47 with a suitableamine (RR′NH) may be used to obtain a final product of interest (50).Similarly, a standard coupling reaction may be used to convertcarboxylic acid 48 to amide 51, which may be another example of thepresent invention when R and R′ are selected appropriately.

Scheme 10 also illustrates the coupling of chlorides 45 and 49 with asuitable partner (XH), usually under basic conditions, to give othercompounds of the present invention (52 and 53). The precise nature ofRR′NH or XH not only determines the identity of the final compound ofinterest, but also influences the choice of conditions under which thereaction is performed. For example, reductive amination of 47 may beperformed using alternative conditions to those shown in Scheme 10, suchas sodium cyanoborohydride in MeOH, depending on the exact natures of 47and the amine. Similarly, the coupling of RR′NH and acid 48 may becarried out under a variety of known conditions, such as use of analternative coupling reagent like PyBOP, or activation of the carboxylicacid as an acid anhydride or acid chloride. One skilled in the art willinfer from precedent in the chemical literature, and from those examplesgiven herein, suitable conditions for reaction of either 45 or 49 withXH, which is usually an amine, lactam or similar compound.

In some cases, compounds of the present invention may be obtained by useof the methodology shown in Scheme 11. Reaction of aldehyde 47 with anappropriate organometallic species (RM), such as a Grignard reagentRMgBr, may be used to give alcohol 54. A wide variety of known couplingreactions that employ transition metal catalysts may also be used tocouple chloride 45 to a suitable partner RX to give 55. Depending uponthe nature of the desired product 55, RX may be chosen from a variety ofuseful coupling partners, such as boronic acids, halides, ororganometallic reagents. In Scheme 11, a palladium catalyst is used butalternatives such as nickel catalysts may also provide the compounds ofinterest. A variety of ligands may be utilized with such metalcatalysts, as described in the literature.

Scheme 12 demonstrates how some other heterocyclic structures may beobtained from diamine precursors. The phenylenediamine 56 can be coupledto an acid RCO₂H using well-known coupling reagents, such as BOP, togive an anilide intermediate which may be cyclized in situ under acidicconditions to give the benzimidazole 57. The same starting material 56can be condensed with a suitable ketoaldehyde, as shown in Scheme 12, togive the quinoxaline product 58. The required ketoaldehyde may besynthesized using known methodology. It may be a derivative of one ofthe coupling partners described herein, or subsequent functionalizationafter quinoxaline formation may be required to provide the desiredcompound of the present invention. Other ring sizes may also beobtained. For example, diamine 59 reacts readily with a variety ofimidate esters to afford dihydrobenzodiazepine products of structure 60.The requisite imidate ester intermediate may be obtained using knownmethodology, such as treatment of the corresponding nitrile with analcohol under acidic conditions.

In Schemes 10-12, a number of strategies for assembling the compounds ofthe present invention are illustrated. It is understood that alternativemethodologies may also be employed in the synthesis of compounds ofinterest. The exact choice of reagents, solvents, temperatures, andother reaction conditions, depends upon the nature of the intendedproduct. In some cases, appropriate protecting group strategies may beused. In other cases, further elaboration of the product shown inSchemes 10-12 may be required to obtain the compound of the presentinvention. As previously stated, the identity of the coupling partner(e.g. RR′NH, XH, or RCO₂H) in Schemes 10-12 must be chosen appropriatelyto give the compounds of the present invention. Some representativeexamples of the synthesis of such coupling partners are shown in thefollowing Schemes.

Scheme 13 illustrates a route to the tricyclic oxindole 104. The4-nitroindole 100 may be oxidized using N-chlorosuccinimide, followed bytreatment with phosphoric acid in acetic acid to give the correspondingoxindole 101. A one-pot dialkylation procedure in DMF, using sodiumhydride as base, can be used to provide the ester intermediate 102. Avariety of R² substituents may be incorporated using this method. Forexample, when R²X is iodomethane the 3-methyloxindole derivative (102;R²=Me) is obtained. Reduction of the nitro group via catalytichydrogenation provides the aniline 103. This nitro reduction may also beeffected using a wide range of conditions that are well known to thoseskilled in the art, including use of zinc, iron, or tin under acidicconditions or reduction with Raney nickel. Cyclization of 103, usuallycarried out by heating in xylenes in the presence of acid, affords thetricyclic oxindole 104.

Scheme 14 describes the conversion of ester 102 (from Scheme 13) into atricyclic indoline. Treatment with Lawesson's reagent transforms 102into the corresponding thioamide 105. This intermediate may be reducedusing, for example, nickel boride or activated Raney nickel to give theaminoindoline 106, which is converted to the tricyclic 107 upon heatingin xylenes in the presence of acid.

An alternative tricyclic oxindole is described in Scheme 15. Themethodology is very similar to that shown in Scheme 13, with theexception that the oxindole 101 is monoalkylated instead of beingdialkylated in the initial alkylation reaction. The resulting ester 108is advanced using identical methodology to that previously described togive the tricyclic oxindole 109. Aromatization of 109 can beaccomplished using a variety of mild oxidation reagents, such as MnO₂ intoluene, to give the tricyclic intermediate 110.

In some cases, it is desirable to perform the couplings shown in Schemes10-12 with a non-tricyclic intermediate and convert the product of thiscoupling to a tricyclic compound in a subsequent step. A representativeexample of such an intermediate is shown in Scheme 16.2-Choro-3-nitrobenzoic acid 111 is reacted with methyl glycinate intert-butanol to give the anthranilic acid derivative 112. Treatment of112 with diphenylphosphoryl azide under basic conditions initially givesthe corresponding acyl azide, which undergoes a Curtius rearrangementthat leads to the benzimidazolone 113. Intermediate 113 may be coupledwith a number of the spirohydantoins described herein. Subsequentreduction of the nitro group and cyclization, in analogy with otherexamples in these schemes, may yield a compound of the presentinvention.

A route to other benzimidazolone intermediates is shown in Scheme 17.The starting material is the 3-nitro-1,2-phenylenediamine 114, which maybe obtained from a variety of published routes and known methodologies(for example Leibigs Ann. Chem. 1989, 539-544; J Med. Chem. 1995, 38,4367-4379). In this scheme, 114 is treated with p-toluenesulfonylchloride, followed by triphosgene, to give the protectednitrobenzimidazolone 115. Elaboration of 115 is carried out in analogywith previous schemes to provide the tricyclic benzimidazolone 117,which may be alkylated on the anilide nitrogen to give a number ofpossible products. In the example shown, alkylation with iodomethane iscarried out in DMF to provide the N-methylated analogue. Deprotectionmay be effected with sulfuric acid to provide the tricyclic intermediate118.

Scheme 18 illustrates a general route to substituted benzimidazolonetricyclic carboxylic acid 124. Starting with the appropriatelysubstituted 3-nitro-1,2-phenylenediamine starting material 114, thenitrobenzimidazolone 119 may be synthesized by treatment with phosgeneor one of a number of carbonylation reagents, includingcarbonyldiimidazole and urea. Alternatively, a substitutedbenzimidazolone may be nitrated in order to provide 119 (J. Org. Chem.1995, 60, 1565-1582).

Alkylation of the nitrobenzimidazolone 119 under basic conditions with asuitable bromoacetate, such as tert-butyl bromoacetate, can afford themonoacetyl derivative 120. Further alkylation of the benzimidazolone isaccomplished using, for example, sodium hydride as base followed by asuitable bromide to give the benzimidazolone 121. In the example shown,bromo esters with different chain lengths may be used to provide anumber of different products. In some cases, depending upon theselection of R¹, these alkylations may result in mixtures ofregioisomers, and the mixtures of 120 or 121 may be separable bychromatography. Reduction of the nitro compound 121 to the correspondinganiline may be accomplished via a number of standard methods, such ascatalytic hydrogenation, and the aniline may be cyclized to give anilide122 under acidic conditions. In Scheme 18, the resultant anilide isN-alkylated to give 123. For example, when R²X is iodomethane, theN-methyl analogue is obtained. Alternatively, the anilide nitrogen maybe arylated using well-precedented methodology, such as treatment withan aryl bromide and a copper or palladium catalyst (Org. Lett. 2000, 2,1101-1104; J. Am. Chem. Soc. 2001, 123, 7727-7729). Hydrolysis of theester to reveal the acid functionality in 124 can be accomplished usingeither acidic or basic conditions, depending upon the nature of theester intermediate 123. In Scheme 18, the tert-butyl ester is removedusing trifluoroacetic acid.

Scheme 19 illustrates a general route to substituted indole tricyclicderivative 131. The nitroindole 100 can be converted to the nitrite 126via a two-step sequence: a Mannich reaction withN,N,N′,N′-tetramethyldiaminomethane followed by treatment with potassiumcyanide. Alternatively, the dimethylamine derivative 125 can be formedby reaction of the nitroindole 100 with dimethylamine and formaldehydein a microwave reactor. N-alkylation of 126 can be accomplished bytreatment with an appropriate alkylating agent under basic conditions togive esters of the general form 127. Treatment of 127 with excess sodiumhydroxide may be used to hydrolyze both the nitrite and ester groups, toafford the diacid 128. Subjection of this diacid to classicalesterification using EtOH and H₂SO₄ converts it to the correspondingdiester 129. The nitro moiety may be reduced under a variety ofconditions, such as catalytic hydrogenation, and the resulting anilinecan be heated under acidic conditions to afford the tricyclic indole130. Saponification of the ester is thereafter accomplished understandard conditions to provide the acid intermediate 131.

The preparation of substituted indoline tricyclic derivatives isoutlined in Scheme 20. Acylation of nitroindole 100 using Vilsmeiermethodology yields the 3-substituted indole 132. Simultaneous reductionof the ketone and the indole may be accomplished using triethylsilaneunder acidic conditions to afford the indoline 133. N-Alkylation of 133can be achieved by treatment with excess ethyl bromoacetate in thepresence of potassium carbonate and potassium iodide to give the ester134. Further elaboration of 134 may be carried out in analogy withprevious schemes to provide the indoline acid intermediate 137.

Another route to substituted indoline tricyclic derivatives is shown inScheme 21. Following condensation of dimethyl malonate withdinitrochlorobenzene 138, treatment of the product 139 with LiCl in wetDMSO provides the phenylacetate derivative 140. Alkylation of compound140 with ethyl bromoacetate affords the succinate 141, and sequentialnitro reduction and acid-catalyzed cyclization affords the tricycle 142.Treatment of 142 with base followed by an electrophile R²X provides thesubstituted derivative 143, which may be selectively reduced to theindoline 144 using DIBAL-H. Simple modifications of these routes,including different protecting group strategies, application ofwell-precedented methodology, and the use of starting materials andreagents other than those described in the foregoing schemes, may beused to provide other acids of interest.

In some cases the final product may be further modified, for example, bymanipulation of substituents. These manipulations may include, but arenot limited to, reduction, oxidation, alkylation, acylation, andhydrolysis reactions which are commonly known to those skilled in theart.

In some cases the order of carrying out the foregoing reaction schemesmay be varied to facilitate the reaction or to avoid unwanted reactionproducts. The following examples are provided so that the inventionmight be more fully understood. These examples are illustrative only andshould not be construed as limiting the invention in any way.

(±)-6′-Carboxy-3′,4′-dihydro-1′H-spiro[imidazolidine-4,2′-naphthalene]-2,5-dioneStep A.(±)-6′-Bromo-3′,4′-dihydro-1′H-spiro[imidazolidine-4,2′-naphthalene]-2,5-dione

A stirred mixture of 6-bromo-2-tetralone (17.6 g, 78.2 mmol), sodiumcyanide (9.58 g, 195 mmol), and ammonium carbonate (97.7 g, 1.02 mol) inH₂O (100 mL) and EtOH (100 mL) was heated to 70° C. for 3 h, thenallowed to cool to ambient temperature. The precipitate was collected byfiltration and washed with H₂O (5×200 mL). Drying in vacuo afforded thetitle compound. MS: m/z 297 (M+1).

Step B.(±)-6′-Carboxy-3′,4′-dihydro-1′H-spiro[imidazolidine-4,2′-naphthalene]-2,5-dione

To a stirred suspension of(±)-6′-bromo-3′,4′-dihydro-1′H-spiro[imidazolidine-4,2′-naphthalene]-2,5-dione(14.9 g, 50.5 mmol) in TM (1.2 L), at −70° C., was added dropwise ethylmagnesium bromide (3.0 M in THF, 51 mL, 152 mmol). The resulting mixturewas stirred for 10 min, then tert-butyllithium (1.7 M in pentane, 180mL, 305 mmol) was added dropwise over 30 min. Stirring was continued at−70° C. for 20 min, then additional tert-butyllithium (1.7 M in pentane,60 mL, 102 mmol) was added dropwise over 10 min. After a further 30 min,CO₂ (g) was bubbled into the reaction mixture until LCMS analysisindicated complete reaction. The mixture was allowed to warm slowly toambient temperature and the THF was removed in vacuo. The residue wassuspended in H₂O and the solution was adjusted to pH=1-2 by the additionof conc. hydrochloric acid, to a final volume of about 500 mL. Themixture was filtered and the isolated solid was washed with H₂O (4×100mL) then dried in vacuo. Trituration of this crude solid with EtOHprovided the title compound. MS: m/z=261 (M+1).

(±)-6′-Amino-3′,4′-dihydro-1′H-spiro[imidazolidine-4,2′-naphthalene]-2,5-dioneStep A.(±)-6′-Amino-3′,4′-dihydro-1′H-spiro[imidazolidine-4,2′-naphthalene]-2,5-dione

A stirred mixture of(±)-6′-carboxy-3′,4′-dihydro-1′H-spiro[imidazolidine-4,2′-naphthalene]-2,5-dione(described in Intermediate 1) (1.50 g, 5.76 mmol), and sodium azide (749mg, 11.53 mmol) in conc. H₂SO₄ (30 mL) was heated to 50° C. for 2 h,then allowed to cool to ambient temperature. The mixture was adjusted topH 8 by addition of 6 N aqueous NaOH and concentrated in vacuo toprecipitate a solid. The precipitate was collected by filtration andwashed extensively with H₂O. Drying in vacuo afforded the titlecompound. MS: m/z=232 (M+1).

(±)-6′-Carboxy-3-methyl-3′,4′-dihydro-1′H-spiro[imidazolidine-4,2′-naphthalene]-2,5-dioneStep A.(±)-6′-Bromo-3-methyl-3′,4′-dihydro-1′H-spiro[imidazolidine-4,2′-naphthalene]-2,5-dione

A mixture of 6-bromo-2-tetralone (1.00 g, 4.44 mmol) and methylaminehydrochloride (300 mg, 4.44 mol) in H₂O (1 mL) and EtOH (1.5 mL) wasstirred at ambient temperature for 20 min. Potassium cyanide (289 mg,4.44 mmol) was added and stirring was continued for 18 h. The mixturewas added dropwise to a stirred solution of 1.0 N aqueous HCl (4.5 mL)at 0° C., then potassium cyanate (360 mg, 4.44 mmol) was addedportionwise. The stirred mixture was heated to 95° C. and conc.hydrochloric acid (0.44 mL) was added dropwise. The reaction mixture washeated at this temperature for 1 h, allowed to cool, and extracted withCH₂Cl₂ (80 mL). The organic extract was dried over Na₂SO₄, filtered, andconcentrated to dryness. The crude product was purified by silica gelchromatography, eluting with a gradient of CH₂Cl₂:MeOH—100:0 to 90:10,to provide a crude sample of the title compound (ca. 70% pure).Trituration with EtOH afforded the title compound. MS: m/z=311 (M+1).

Step B.(±)-6′-Carboxy-3-methyl-3′,4′-dihydro-1′H-spiro[imidazolidine-42′-naphthalene]-2,5-dione

To a stirred suspension of(±)-6′-bromo-3-methyl-3′,4′-dihydro-1′H-spiro[imidazolidine-4,2′-naphthalene]-2,5-dione(211 mg, 0.682 mmol) in THF (30 mL), at −70° C., was added dropwiseethyl magnesium bromide (1.0 M in THF, 1.37 mL, 1.37 mmol). Theresulting mixture was stirred for 15 min, then tert-butyllithium (1.7 Min pentane, 1.61 mL, 2.73 mmol) was added dropwise. After a further 30min, CO₂ (g) was bubbled into the reaction mixture until LCMS analysisindicated complete reaction. The mixture was allowed to warm slowly toambient temperature and the THF was removed in vacuo. The residue wassuspended in H₂O (20 mL) and the solution was adjusted to pH=1-2 by theaddition of 1.0 N hydrochloric acid, then it was saturated with NaCl(s). The mixture was filtered and the isolated solid was washed with H₂Othen dried in vacuo. Trituration of this crude solid with EtOH providedthe title compound. MS: m/z=275 (M+1).

(±)-7′-Amino-3′,4′-dihydro-1′H-spiro[imidazolidine-4,2′-naphthalene]-2,5-dioneStep A. 7-Bromo-2-tetralone

A solution of 3-bromophenylacetic acid (10.4 g, 48.4 mmol) in oxalylchloride (50 mL, 0.57 mol) was stirred at ambient temperature for 5 minthen at reflux for 5 h. The oxalyl chloride was removed in vacuo and theresidue was dissolved in anhydrous CH₂Cl₂ (100 mL). This solution wasadded dropwise to a rapidly stirred, ice-cooled solution of AlCl₃ (23.2g, 174.2 mmol) in CH₂Cl₂ (500 mL). A stream of ethylene gas was blowninto the vortex of the stirred solution during the addition and thereaction temperature was kept at <5° C. The reaction mixture was allowedto warm to ambient temperature and then poured onto ice and stirredvigorously. The organic portion was removed and the aqueous layerextracted with CH₂Cl₂ (2×200 mL). The combined CH₂Cl₂ fractions werepassed through a 2″ pad of silica and concentrated to give a thick, redoil. The crude product was purified by silica gel chromatography,eluting with a gradient of hexane:EtOAc—100:0 to 75:25, to provide thetitle compound. MS: m/z=226 (M+1).

(±)-7′-Amino-3′,4′-dihydro-1′H-spiro[imidazolidine-4,2′-naphthalene]-2,5-dione

Essentially following the procedures described for Intermediate 1 andIntermediate 2, but using 7-bromo-2-tetralone in place of6-bromo-2-tetralone,(±)-7′-amino-3′,4′-dihydro-1′H-spiro[imidazolidine-4,2′-naphthalene]-2,5-dionewas prepared. MS: m/z=232 (M+1).

(±)Spiro[imidazolidine-4,2′-indane]-2,5-dione Step A.(±)-Spiro[imidazolidine-4,2′-indane]-2,5-dione

A stirred mixture of 2-indanone (3.0 g, 22.6 mmol), sodium cyanide (3.3g, 67.3 mmol), and ammonium carbonate (22 g, 228 mol) in H₂O (50 mL) andEtOH (50 mL) was heated to 70° C. for 3 h, then allowed to cool toambient temperature. The precipitate was collected by filtration andwashed with H₂O (5×100 mL). Drying in vacuo afforded the title compound.MS: m/z=202 (M+1).

(±)-5′-Amino-spiro[imidazolidine-4,2′-indane]-2,5-dione Step A.(±)-5′-Nitro-spiro[imidazolidine-4,2′-indane]-2,5-dione

A solution of (±)-spiro[imidazolidine-4,2′-indane]-2,5-dione (3.0 g,14.8 mmol, described in Intermediate 5) in conc. nitric acid (33 mL) wasstirred at ambient temperature for 1 h. The reaction was then pouredonto crushed ice and the resultant solid was isolated by filtration. Thecrude material was recrystallized from ethanol to give the titlecompound. MS: m/z=248 (M+1).

Step B. (±)-5′-Amino-spiro[imidazolidine-4,2′-indane]-2,5-dione

To a suspension of(±)-5′-nitro-spiro[imidazolidine-4,2′-indane]-2,5-dione (1.77 g, 7.16mmol) in EtOAc (100 mL) and MeOH (100 mL) was added 10% Pd/C (400 mg)and the reaction stirred vigorously under hydrogen (ca. 1 atm). After 1h, the catalyst was filtered off and the filtrate was concentrated toyield the title compound. MS: m/z=218 (M+1).

(±)-5′-Amino-3-methyl-spiro[imidazolidine-4,2′-indane]-2,5-dione Step A.2-(Methylamino)indane-2-carbonitrile Hydrochloride

To a mixture of 2-indanone (20.0 g, 151 mmol) in MeOH (20 mL) was addedmethylamine hydrochloride (10.2 g, 151 mmol). To the stirred mixture wasadded H₂O (20 mL) and a fine homogenous slurry developed. The reactionmixture was cooled to 0° C. and KCN (9.84 g, 151 mmol) in H₂O (20 mL)was added slowly over 30 min, such that the temperature did not exceed10° C., then stirring was continued at ambient temperature for 18 h. Thereaction mixture was extracted with Et₂O (250 mL) and the organicextract was washed with brine (50 mL) then dried over MgSO₄. HCl (g) wasbubbled through the vigorously stirred solution for 10 minutes and asolid precipitated. The solid was filtered, washed with Et₂O, and driedto yield the title compound. MS: m/z=173 (M+1).

Step B. (±)-3-Methyl-spiro[imidazolidine-4,2′-indane]-2,5-dione

To a stirred mixture of 2-(methylamino)indane-2-carbonitrilehydrochloride from Step A (6.0 g, 28.8 mmol) in AcOH (45 mL) was added asolution of potassium cyanate (4.65 g, 57 mmol) in H₂O (6 mL) and thereaction mixture was stirred for 1 h. The mixture was poured into coldH₂O (150 mL) and the precipitate was isolated by filtration, washed withH₂O and air dried. The crude solid was suspended in 1 N HCl (30 mL) andstirred to 50° C. for 2 h. The reaction mixture was cooled, filtered,and the isolated solid washed with H₂O and dried in vacuo to yield thetitle compound. MS: m/z=217 (M+1).

Step C. (±)-3-Methyl-5′-nitro-spiro[imidazolidine-4,2′-indane]-2,5-dione

To stirred fuming (90%) nitric acid (100 mL) was slowly added(±)-3-methyl-spiro[imidazolidine-4,2′-indane]-2,5-dione (4.5 g, 20.9mmol) in portions over 30 min. The reaction mixture was diluted with H₂O(200 mL) and the precipitate was collected by filtration, washed withH₂O and dried in vacuo to give the title compound. MS: m/z=262 (M+1).

(±)-5′-Amino-3-methyl-spiro[imidazolidine-4,2′-indane]-2,5-dione

Essentially following the procedures described for Intermediate 6, butusing (±)-3-methyl-5′-nitro-spiro[imidazolidine-4,2′-indane]-2,5-dionein place of (±)-5′-nitro-spiro[imidazolidine-4,2′-indane]-2,5-dione, thetitle compound was prepared. MS: m/z=232 (M+1).

(R)-5′-Amino-3-methyl-spiro[imidazolidine-4,2′-indane]-2,5-dione Step A.(R)-3-Methyl-5′-nitro-spiro[imidazolidine-4,2′-indane]-2,5-dione

(±)-3-Methyl-5′-nitro-spiro[imidazolidine-4,2′-indane]-2,5-dione(described in Intermediate 7) was dissolved in a mixture of MeOH, CH₃CNand diethylamine and the enantiomers were resolved by HPLC, utilizing aChiralPak AD column and eluting with CH₃CN:MeOH—90:10. The first majorpeak to elute was(S)-3-methyl-5′-nitro-spiro[imidazolidine-4,2′-indane]-2,5-dione and thesecond major peak to elute was(R)-3-methyl-5′-nitro-spiro[imidazolidine-4,2′-indane]-2,5-dione, thetitle compound. MS: m/z=262 (M+1).

(R)-5′-Amino-3-methyl-spiro[imidazolidine-4,2′-indane]-2,5-dione

Essentially following the procedures described for Intermediate 6, butusing (R)-3-methyl-5′-nitro-spiro[imidazolidine-4,2′-indane]-2,5-dionein place of (±)-5′-nitro-spiro[imidazolidine-4,2′-indane]-2,5-dione, thetitle compound was prepared. MS: m/z=232 (M+1).

(S)-5′-Amino-6′-chloro-3-methyl-spiro[imidazolidine-4,2′-indane]-2,5-dioneStep A.(S)-5′-Amino-6′-chloro-3-methyl-spiro[imidazolidine-4,2′-indane]-2,5-dione

(R)-5′-Amino-3-methyl-spiro[imidazolidine-4,2′-indane]-2,5-dione (265mg, 1.15 mmol, described in Intermediate 8) was dissolved in AcOH (7 mL)and N-chlorosuccinimide (145 mg, 1.09 mmol) was added in one portion.The mixture was stirred at ambient temperature for 5 h, then the solventwas removed in vacuo. The residue was partitioned between saturatedaqueous NaHCO₃ (20 mL) and CH₂Cl₂ (70 mL). The organic layer was dried(Na₂SO₄), filtered, and concentrated under reduced pressure. The crudeproduct was purified by silica gel chromatography, eluting with agradient of CH₂Cl₂:EtOAc—100:0 to 0:100, to give(R)-5′-amino-4′-chloro-3-methyl-spiro[imidazolidine-4,2′-indane]-2,5-dione,which eluted first, and the title compound, which eluted second. MS:m/z=266 (M+1).

(R)-5′-Amino-4′-chloro-3-methyl-spiro[imidazolidine-4,2′-indane]-2,5-dioneStep A.(R)-5′-Amino-4′-chloro-3-methyl-spiro[imidazolidine-4,2′-indane]-2,5-dione

The title compound was obtained from the same reaction as Intermediate9. The crude product was purified by silica gel chromatography, elutingwith a gradient of CH₂Cl₂:EtOAc—100:0 to 0:100, to give the titlecompound, which eluted first, and(S)-5′-amino-6′-chloro-3-methyl-spiro[imidazolidine-4,2′-indane]-2,5-dione,which eluted second. MS: m/z 266 (M+1).

(±)-5′-Amino-3-(benzyl)-spiro[imidazolidine-4,2′-indane]-2,5-dione StepA.(±)-1-(4-Methoxybenzyl)-5′-nitro-spiro[imidazolidine-4,2′-indane]-2,5-dione

A mixture of (±)-5′-nitro-spiro[imidazolidine-4,2′-indane]-2,5-dione(1.4 g, 5.66 mmol, described in Intermediate 6), 4-methoxybenzyl alcohol(0.94 g, 6.80 mmol), diethyl azodicarboxylate (1.48 g, 8.49 mmol), andtriphenylphosphine (2.23 g, 8.49 mmol) in THF (15 mL) was stirred atambient temperature for 3 days. The solvent was removed under reducedpressure and the residue was partitioned between saturated aqueousNaHCO₃ (15 mL) and CH₂Cl₂ (50 mL). The organic layer was dried (Na₂SO₄),filtered, and concentrated under reduced pressure. The crude product waspurified by silica gel chromatography, eluting with a gradient ofhexane:EtOAc—90:10 to 60:40, to give the title compound. MS: m/z=368(M+1).

Step B.(±)-3-Benzyl-1-(4-methoxybenzyl)-5′-nitro-spiro[imidazolidine-4,2′-indane]-2,5-dione

To a solution of(±)-1-(4-methoxybenzyl)-5′-nitro-spiro[imidazolidine-4,2′-indane]-2,5-dionefrom Step A (165 mg, 0.45 mmol) in DMF (1 mL) was added sodium hydride(18 mg of a 60% dispersion in mineral oil, 0.45 mmol). The mixture wasstirred for 5 min at ambient temperature and benzyl bromide (230 mg,1.35 mmol) was added. After 30 min, the mixture was partitioned betweensaturated aqueous NaHCO₃ (3 mL) and CHCl₃ (5 mL). The aqueous phase wasextracted further with CHCl₃ (5 mL) and the combined organic layers weredried (Na₂SO₄), filtered, and concentrated under reduced pressure. Thecrude product was purified by silica gel chromatography, eluting withhexane:EtOAc—75:25, to give the title compound. MS: m/z=458 (M+1).

Step C. (±)-3-Benzyl-5′-nitro-spiro[imidazolidine-4,2′-indane]-2,5-dione

To a stirred solution of(±)-3-benzyl-1-(4-methoxybenzyl)-5′-nitro-spiro[imidazolidine-4,2′-indane]-2,5-dionefrom Step B (110 mg, 0.24 mmol) in acetonitrile (1.5 mL) was addeddropwise a solution of ammonium cerium (IV) nitrate (395 mg, 0.72 mmol)in H₂O (1 mL). After 3 h at ambient temperature, the precipitate wasisolated by filtration and dried in vacuo to afford the title compound.MS: m/z=338 (M+1).

Step D. (±)-5′-Amino-3-benzyl-spiro[imidazolidine-4,2′-indane]-2,5-dione

To a solution of(±)-3-benzyl-5′-nitro-spiro[imidazolidine-4,2′-indane]-2,5-dione fromStep C (80 mg, 0.24 mmol) in EtOAc (1.5 mL) and MeOH (1.5 mL) was added10% Pd/C (5 mg) and the reaction mixture was stirred vigorously underhydrogen (ca. 1 atm). After 18 h, the catalyst was filtered off and thefiltrate was concentrated to yield the title compound. MS: m/z=308(M+1).

(±)-5′-Amino-3-(2-methylprop-1-yl)-spiro[imidazolidine-4,2′-indane]-2,5-dione

Essentially following the procedures described for Intermediate 11, butusing 1-bromo-2-methylpropane in place of benzyl bromide, the titlecompound was prepared. MS: m/z 274 (M+1).

(7R)-3′-Methyl-2′,5′-dioxo-6,8-dihydrospiro[cylopenta[g]quinoline-7,4′-imidazolidine]-2-carbaldehydeStep A.(7R)-2,3′-Dimethyl-6,8-dihydro-2H,5H-spiro[cyclotenta[g]quinoline-74′-imidazolidine]-2′,5′-dione

(R)-5′-Amino-3-methyl-spiro[imidazolidine-4,2′-indane]-2,5-dione (3.00g, 13.0 mmol, described in Intermediate 8) and p-chloranil (3.19 g, 13.0mmol) were suspended in a mixture of 1-BuOH (3.2 mL) and conc.hydrochloric acid (3.2 mL, 39 mmol), and the mixture was heated toreflux. Crotonaldehyde (1.09 g, 15.6 mmol) in 1-BuOH (3 mL) was addeddropwise over 20 min. After a further 20 min at reflux, the mixture wasallowed to cool to ambient temperature, 10 N NaOH (3.9 mL, 39 mmol) wasadded, and the neutralized mixture was concentrated in vacuo to give abrown residue. The crude product was purified by silica gelchromatography, eluting with a gradient of CH₂Cl₂:MeOH—100:0 to 90:10,to give the title compound. MS: m/z=282 (M+1).

Step B.(7R)-3′-Methyl-2′,5′-dioxo-6,8-dihydrospiro[cyclopenta[g]quinoline-7,4′-imidazolidine]-2-carbaldehyde

A mixture of(7R)-2,3′-dimethyl-6,8-dihydro-2H,5H-spiro[cyclopenta[g]quinoline-7,4′-imidazolidine]-2′,5′-dionefrom Step A (1.70 g, 6.04 mmol), selenium dioxide (1.01 g, 9.06 mmol)and powdered molecular sieves, 4 Å, (680 mg) in dioxane (60 mL) washeated at reflux for 90 min. The reaction mixture was filtered through apad of Celite, washing with CH₂Cl₂-MeOH, and the filtrate wasconcentrated under reduced pressure. The residue was partitioned betweensaturated aqueous NaHCO₃ (400 mL) and EtOAc (1.5 L) containing MeOH (30mL). The organic layer was extracted and the aqueous layer was washedwith EtOAc (400 mL). The combined organic layers were washed with brine,dried over Na₂SO₄, filtered, and concentrated in vacuo to give the titlecompound. MS: m/z=296 (M+1).

(7R)-2-(Chloromethyl)-3′-methyl-6,8-dihydro-2′H,5H-spiro[cyclopenta[g]quinoline-7,4′-imidazolidine]-2′,5′-dioneStep A.(7R)-2-(Hydroxymethyl)-3′-methyl-6,8-dihydro-2H,5H-spiro[cyclopenta[g]quinoline-7,4′-imidazolidine]-2′,5′-dione

To a stirred solution of(7R)-3′-methyl-2′,5′-dioxo-6,8-dihydrospiro[cyclopenta[g]quinoline-7,4′-imidazolidine]-2-carbaldehyde(2.62 g, 8.89 mmol, described in Intermediate 13) in MeOH (20 mL) wasadded NaBH₄ (672 mg, 17.8 mmol) and the mixture was stirred at ambienttemperature for 1 h, then concentrated to dryness in vacuo. The crudeproduct was purified by silica gel chromatography, eluting with agradient of CH₂Cl₂:MeOH:NOH—100:0:0 to 90:9:1, to give the titlecompound. MS: m/z=298 (M+1).

Step B.(7R)-2-(Chloromethyl)-3′-methyl-6,8-dihydro-2′H5′H-spiro[cyclopenta[g]quinoline-7,4′-imidazolidine]-2′,5′-dione

To a stirred solution of(7R)-2-(hydroxymethyl)-3′-methyl-6,8-dihydro-2′H,5′H-spiro[cyclopenta[g]quinoline-7,4′-imidazolidine]-2′,5′-dionefrom Step A (200 mg, 0.67 mmol) in CH₂Cl₂ (5 mL) was added thionylchloride (0.98 mL, 13.5 mmol) dropwise. The reaction mixture was stirredfor 30 min and the precipitate was isolated by filtration. The filtratewas poured into saturated aqueous NaHCO₃ (20 mL) and this mixture wasextracted with CH₂Cl₂ (3×30 mL). The combined organic extracts weredried over Na₂SO₄, filtered, and concentrated in vacuo to give a solid,which was combined with the filtered solid to give the title compound,which was of sufficient purity for use in subsequent steps. MS: m/z=316(M+1).

Methyl (7-nitro-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl)acetate Step A.Methyl N-(6-carboxy-2-nitrophenyl)glycinate

A mixture of methyl glycinate (15.9 g, 127 mmol),2-chloro-3-nitrobenzoic acid (6.07 g, 30.1 mmol) and Na₂CO₃ (22.9 g, 216mmol) in tert-BuOH (40 mL) was heated at reflux for 18 h. The cooledmixture was concentrated under reduced pressure and the residue waspartitioned between H₂O (200 mL) and EtOAc (200 mL). The aqueous layerwas acidified to pH 2 and the organic layer was extracted. The aqueouslayer was extracted further with EtOAc (2×200 mL). The combined organicextracts were washed with brine, dried over Na₂SO₄, filtered, andconcentrated in vacuo to give the title compound in sufficient purityfor use in the next step. MS: m/z=255 (M+1).

Step B. Methyl (7-nitro-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl)acetate

A mixture of methyl N-(6-carboxy-2-nitrophenyl)glycinate from Step A(6.08 g, 23.9 mmol), diphenyl phosphoryl azide (7.90 g, 28.7 mmol) andN,N-diisopropylethylamine (12.5 mL, 71.8 mmol) in tert-BuOH (40 mL) washeated at 90° C. for 90 min, then solvent was removed in vacuo. Theresidue was purified by silica gel chromatography, eluting with agradient of CH₂Cl₂:MeOH—100:0 to 90:10, to give the title compound insufficient purity for use in subsequent steps. MS: m/z=252 (M+1).

2a-Methyl-2a,5-dihydropyrrolo[4,3,2-de]quinoline-2,4(1H,3H)-dione,enantiomer B Step A. 4-Nitro-1,3-dihydro-2H-indol-2-one

A mixture of 4-nitroindole (12.2 g, 75.2 mmol) and N-chlorosuccinimide(6.07 g, 30.1 mmol) in CHCl₃ (500 mL) was heated at reflux for 30 h,then concentrated under reduced pressure to give an orange solid. Thesolid was dissolved in AcOH (200 mL) and the resulting solution waswarmed to 70° C., then 85% H₃PO₄ (80 mL) was added over 2 min. Themixture was heated to reflux for 90 min then cooled on ice. The cooledmixture was adjusted to pH 6 by addition of 10 N NaOH (450 mL), followedby aqueous NaHCO₃, keeping the temperature below 30° C. The mixture wasextracted with EtOAc (3×1 L) and the combined organic extracts weredried over Na₂SO₄, filtered, and concentrated in vacuo. The crudeproduct was partially purified by silica gel chromatography, elutingwith a gradient of hexane:EtOAc—100:0 to 0:100, and then triturated withMeOH to give the title compound. MS: m/z 179 (M+1).

Step B. (L)-Ethyl(3-methyl-4-nitro-2-oxo-2,3-dihydro-1H-indol-3-yl)acetate

To a stirred solution of 4-nitro-1,3-dihydro-2H-indol-2-one from Step A(6.95 g, 39.0 mmol) in DMF (180 mL) at 0° C. was added sodium hydride(60% dispersion in mineral oil; 1.72 g, 42.9 mmol) and the resultingmixture was stirred for 30 min. Iodomethane (2.43 mL, 39.0 mmol) in DMF(20 mL) was added dropwise over 20 min, and the mixture was stirred at0° C. for 1 h. A further equivalent of sodium hydride (60% dispersion inmineral oil; 1.56 g, 39.0 mmol) was added and stirring was continued for1 h. Ethyl bromoacetate (3.46 mL, 31.2 mmol) in DMF (20 mL) was addeddropwise over 20 min. The reaction mixture was stirred at 0° C. for 1 h,then quenched with saturated aqueous NH₄Cl (500 mL). The mixture wasextracted with EtOAc (3×500 mL) and the combined organic extracts werewashed with brine (100 mL), then dried over Na₂SO₄, filtered, andconcentrated in vacuo. The crude product was purified by silica gelchromatography, eluting with a gradient of hexane:EtOAc—100:0 to 0:100,to give the title compound. MS: m/z=279 (M+1).

Step C. (L)-Ethyl(4-amino-3-methyl-2-oxo-2,3-dihydro-1H-indol-3-yl)acetate

A mixture of (±)-ethyl(3-methyl-4-nitro-2-oxo-2,3-dihydro-1H-indol-3-yl)acetate from Step B(2.66 g, 9.56 mmol) and 10% Pd/C (500 mg) was stirred vigorously in MeOH(50 mL) under an atmosphere of hydrogen (ca. 1 atm). After 3 h, themixture was filtered through a pad of Celite, washing with MeOH, and thefiltrate was concentrated in vacuo to give the title compound. MS:m/z=249 (M+1).

Step D.2a-Methyl-2a,5-dihydropyrrolo[4,3,2-de]quinoline-2,4(1H,3H)-dione,enantiomer B

A mixture of (±)-ethyl(4-amino-3-methyl-2-oxo-2,3-dihydro-1H-indol-3-yl)acetate from Step C(2.37 g, 9.56 mmol) and AcOH (1 mL) was heated in xylenes (10 mL) atreflux for 24 h, then concentrated to dryness under reduced pressure.The crude product was partially purified by silica gel chromatography,eluting with a gradient of CH₂Cl₂:MeOH:NH₄H—100:0:0 to 90:9:1, to give acrude sample of the title compound. Further purification by silica gelchromatography, eluting with a gradient of CH₂Cl₂:EtOAc—100:0 to 0:100,gave the racemic title compound. The enantiomers were resolved by HPLC,utilizing a ChiralPak AS column and eluting with hexane:EtOH—70:30. Thefirst major peak to elute was2a-methyl-2a,5-dihydropyrrolo[4,3,2-de]quinoline-2,4(1H,3H)-dione,enantiomer A, and the second major peak to elute was2a-methyl-2a,5-dihydropyrrolo[4,3,2-de]quinoline-2,4(1H,3H)-dione,enantiomer B, the title compound. MS: m/z=203 (M+1).

Pyrrolo[4,3,2-de]quinoline-2,4(1H,5H)-dione Step A. (±)-Ethyl(4-nitro-2-oxo-2,3-dihydro-1H-indol-3-yl)acetate

To a stirred solution of 4-nitro-1,3-dihydro-2H-indol-2-one (3.00 g,16.8 mmol, described in Intermediate 16) in DMF (100 mL) at 0° C. wasadded sodium hydride (60% dispersion in mineral oil; 740 mg, 18.5 mmol)and the resulting mixture was stirred for 30 min. Ethyl bromoacetate(1.87 mL, 16.8 mmol) in DMF (10 mL) was added dropwise over 10 min. Thereaction mixture was stirred at 0° C. for 2 h, then quenched with H₂O(200 mL). The mixture was extracted with EtOAc (5×200 mL) and thecombined organic extracts were washed with brine (100 mL), then driedover Na₂SO₄, filtered, and concentrated in vacuo. The crude product waspurified by silica gel chromatography, eluting with a gradient ofhexane:EtOAc—100:0 to 0:100, followed by crystallization fromhexane:EtOAc to give the title compound. MS: m/z=265 (M+1).

Step B. (±)-Ethyl (4-amino-2-oxo-2,3-dihydro-1H-indol-3-yl)acetate

A mixture of (±)-ethyl (4-nitro-2-oxo-2,3-dihydro-1H-indol-3-yl)acetatefrom Step A (2.56 g, 9.69 mmol) and 10% Pd/C (500 mg) was stirredvigorously in MeOH (50 mL) under an atmosphere of hydrogen (ca. 1 atm).After 16 h, the mixture was filtered through a pad of Celite, washingwith MeOH, and the filtrate was concentrated in vacuo to give the titlecompound. MS: m/z=235 (M+1).

Step C. (±)-2a,5-Dihydropyrrolo[4,3,2-de]quinoline-2,4(1H,3H)-dione

A mixture of (±)-ethyl (4-amino-2-oxo-2,3-dihydro-1H-indol-3-yl)acetatefrom Step B (2.40 g, 10.2 mmol), p-toluenesulfonic acid (195 mg, 1.03mmol) and AcOH (1 mL) was heated in xylenes (10 mL) at reflux for 24 h,then concentrated to dryness under reduced pressure. The crude productwas partially purified by silica gel chromatography, eluting with agradient of CH₂Cl₂:MeOH:NH₄OH—100:0:0 to 90:9:1, to give a crude sampleof the title compound. Further purification was achieved by triturationwith CH₂Cl₂ to give the title compound. MS: m/z=189 (M+1).

Step D. Pyrrolo[4,3,2-de]quinoline-2,4(1H,5H)-dione

A mixture of (±)-2a,5-dihydropyrrolo[4,3,2-de]quinoline-2,4(1H,3H)-dionefrom Step C (200 mg, 1.06 mmol), and activated manganese (IV) oxide (185mg, 2.13 mmol) was heated in toluene (3 mL) at 110° C. for 1 h. Themixture was filtered through a pad of Celite, washing with CH₂Cl₂:MeOH,and the filtrate was concentrated in vacuo to give the title compound.MS: m/z=187 (M+1).

1,2,2a,5-Tetrahdropyrrolo[4,3,2-de]quinolin-4(3H)-one, Enantiomer B StepA. Ethyl (4-nitro-1H-indol-3 yl)(oxo)acetate

Diphosphoryl chloride (23.5 mL, 170 mmol) was added dropwise to astirred mixture of 4-nitroindole (25.0 g, 154 mmol) and ethyl1-piperidineglyoxylate (29.0 g, 170 mmol) at 0° C. The mixture wasallowed to warm slowly to ambient temperature and stirring was continuedfor 18 h. The reaction mixture was cooled to 0° C. and quenchedcarefully by addition of EtOH (50 mL), followed by saturated aqueousNaBCO₃ until no further effervescence was observed. The precipitatedyellow solid was isolated by filtration, washed with H₂O, and dried invacuo to give the title compound. MS: m/z=263 (M+1).

Step B. Ethel (4-nitro-2,3-dihydro-1H-indol-3-yl)acetate enantiomer B

Triethylsilane (80 mL, 493 mmol) was added dropwise to a solution ofethyl (4-nitro-1H-indol-3-yl)(oxo)acetate from Step A (6.46 g, 24.6mmol) in TFA (100 mL). After 3 h, the reaction mixture was concentratedin vacuo and the residue was purified by silica gel chromatography,eluting with a gradient of CH₂Cl₂:MeOH—100:0 to 99:1, to give theracemic product. The enantiomers were resolved by HPLC, utilizing aChiralcel OD column and eluting with hexane: i-PrOH—70:30. The firstmajor peak to elute was ethyl(4-nitro-2,3-dihydro-1H-indol-3-yl)acetate, enantiomer A, and the secondmajor peak to elute was ethyl(4-nitro-2,3-dihydro-1H-indol-3-yl)acetate, enantiomer B, the titlecompound. MS: m/z=251 (M+1).

Step C. 1,2,2a,5-Tetrahydropyrrolo[4,3,2-de]quinolin-4(3H)-one,Enantiomer B

To a stirred solution of ethyl(4-nitro-2,3-dihydro-1H-indol-3-yl)acetate, enantiomer B, from Step B(1.50 g, 5.99 mmol) in H₂O (50 mL) and EtOH (42 mL) was added sodiumhydrosulfite (ca. 85%; 4.91 g, 24 mmol). The reaction mixture wasstirred at ambient temperature for 1 h, then 3 N hydrochloric acid (14mL, 42 mmol) was added and the solution was heated to 100° C. for 3 h.The cooled mixture was adjusted to pH 8 with saturated aqueous NaHCO₃,then extracted with CH₂Cl₂ (6×200 mL). The combined organic extractswere dried over Na₂SO₄, filtered, and concentrated in vacuo to give thetitle compound. MS: m/z=175 (M+1).

2a-Methyl-1,2,2a,5-tetrahydropyrrolo[4,3,2-de]quinolin-4(3H-one,Enantiomer A Step A.(±)-Ethyl(3-methyl-4-nitro-2-thioxo-2,3-dihydro-1H-indol-3-yl)acetate

A mixture of (±)-ethyl(3-methyl-4-nitro-2-oxo-2,3-dihydro-1H-indol-3-yl)acetate (1.08 g, 3.88mmol, described in Intermediate 16) and Lawesson's reagent (942 mg, 2.33mmol) was heated at reflux in xylenes (30 mL) for 90 min. The reactionmixture was concentrated in vacuo and the residue was purified by silicagel chromatography, eluting with a gradient of CH₂Cl₂:EtOAc—100:0 to90:10, to give the title compound. MS: m/z=295 (M+1).

Step B. (±)-Ethyl (4-amino-3-methyl-2,3-dihydro-1H-indol-3-yl)acetate

To a solution of (±)-ethyl(3-methyl-4-nitro-2-thioxo-2,3-dihydro-1H-indol-3-yl)acetate from Step A(3.65 g, 12.4 mmol) and nickel (II) chloride hexahydrate (23.6 g, 99.2mmol) in MeOH (30 mL) and THF (30 mL), at 0° C., was added NaBH₄ (11.3g, 298 mmol) in portions over 1 h. The resulting mixture was stirred for10 min, then filtered through a pad of Celite, washing with MeOH, andthe filtrate was concentrated in vacuo. The residue was purified bysilica gel chromatography, eluting with CH₂Cl₂:MeOH—90:10, to give thetitle compound. MS: m/z=235 (M+1).

Step C.2a-Methyl-1,2,2a,5-tetrahydropyrrolo[4,3,2-de]quinolin-4(3H)-one,Enantiomer A

A mixture of (±)-ethyl(4-amino-3-methyl-2,3-dihydro-1H-indol-3-yl)acetate from Step B (2.50 g,10.7 mmol) and p-toluenesulfonic acid (2 mg, 0.01 mmol) was heated inxylenes (50 mL) at reflux for 13 h, then concentrated to dryness underreduced pressure. The crude product was purified by silica gelchromatography, eluting with a gradient of CH₂Cl₂:MeOH:N₄OH—100:0:0 to90:4.5:0.5, to give the racemic title compound. The enantiomers wereresolved by HPLC, utilizing a ChiralPak AD column and eluting withhexane: i-PrOH:Et₂NH—75:25:0.1. The first major peak to elute was2a-methyl-1,2,2a,5-tetrahydropyrrolo[4,3,2-de]quinolin-4(3H)-one,enantiomer A, the title compound, and the second major peak to elute was2a-methyl-1,2,2a,5-tetrahydropyrrolo[4,3,2-de]quinolin-4(3H)-one,enantiomer B. MS: m/z=189 (M+1).

Ethyl (4-oxo-1,2,4,5-tetrahydropyrrolo[4,3,2-de]quinolin-2a(3H-yl)acetate, Enantiomer A Step A. Diethyl2,2′-(4-nitro-2-oxo-2,3-dihydro-1H-indol-3,3-diyl)diacetate

To a stirred solution of 4-nitro-1,3-dihydro-2H-indol-2-one (5.25 g,29.5 mmol, described in Intermediate 16) in DMF (200 mL) at 0° C. wasadded sodium hydride (60% dispersion in mineral oil; 1.24 g, 30.9 mmol)and the resulting mixture was stirred for 30 min. Ethyl bromoacetate(3.60 mL, 32.4 mmol) was added dropwise and the mixture was stirred at0° C. for 1 h. A further equivalent of sodium hydride (60% dispersion inmineral oil; 1.24 g, 30.9 mmol) was added, stirring was continued for 1h, then ethyl bromoacetate (3.00 mL, 27.1 mmol) was added dropwise. Thereaction mixture was stirred for 1 h, then quenched with saturatedaqueous NH₄Cl (125 mL) and H₂O (500 mL). The mixture was extracted withEtOAc (3×300 mL) and the combined organic extracts were washed withbrine (100 mL), then dried over Na₂SO₄, filtered, and concentrated invacuo. The crude product was purified by silica gel chromatography,eluting with a gradient of hexane:EtOAc—100:0 to 50:50, to give thetitle compound. MS: m/z=351 (M+1).

Ethyl(4-oxo-1,2,4,5-tetrahydropyrrolo[4,3,2-de]quinolin-2a(3H)-yl)acetate,Enantiomer A

Essentially following the procedures described for Intermediate 19, butusing diethyl2,2′-(4-nitro-2-oxo-2,3-dihydro-1H-indol-3,3-diyl)diacetate from Step Ain place of (±)-ethyl(3-methyl-4-nitro-2-oxo-2,3-dihydro-1H-indol-3-yl)acetate, the racemictitle compound was prepared. The enantiomers were resolved by HPLC,utilizing a ChiralPak AD column and eluting withhexane:EtOH:Et₂NH—75:25:0.1. The first major peak to elute was ethyl(4-oxo-1,2,4,5-tetrahydropyrrolo[4,3,2-de]quinolin-2a(3H)-yl)acetate,enantiomer A, the title compound, and the second major peak to elute wasethyl(4-oxo-1,2,4,5-tetrahydropyrrolo[4,3,2-de]quinolin-2a(3H)-yl)acetate,enantiomer B. MS: m/z=261 (M+1).

(7R)-9-Bromo-3′-methyl-2′,5′-dioxo-6,8-dihydrospiro[cyclopenta[g]quinoline-7,4′-imidazolidine]-2-carbaldehydeStep A.(7R)-9-Bromo-2,3′-dimethyl-6,8-dihydro-2′H5′H-spiro[cyclopenta[g]quinoline-7,4′-imidazolidine]-2′,5′-dione

To a stirred solution of(7R)-2,3′-dimethyl-6,8-dihydro-2′H,5′H-spiro[cyclopenta[g]quinoline-7,4′-imidazolidine]-2′,5′-dione(250 mg, 0.89 mmol, described in Intermediate 13) in conc. sulfuric acid(1 mL) was added N-bromosuccinimide (206 mg, 1.16 mmol). The reactionmixture was stirred for 6 h, poured onto ice, neutralized with saturatedaqueous NaHCO₃, and extracted with EtOAc (2×100 mL). The combinedorganic extracts were dried over Na₂SO₄, filtered, and concentrated invacuo. The crude product was purified by HPLC, utilizing a Chiralcel OJcolumn and eluting with MeOH. The first major peak to elute was thetitle compound. MS: m/z=362 (M+1).

(7R)-9-Bromo-3′-methyl-2′,5′-dioxo-6,8-dihydrospiro[cyclopenta[g]quinoline-7,4′-imidazolidine]-2-carbaldehyde

Essentially following the procedures described for Intermediate 13, butusing(7R)-9-bromo-2,3′-dimethyl-6,8-dihydro-2H,5H-spiro[cyclopenta[g]quinoline-7,4′-imidazolidine]-2′,5′-dionefrom Step A in place of(7R)-2,3′-dimethyl-6,8-dihydro-2H,5H-spiro[cyclopenta[g]quinoline-7,4′-imidazolidine]-2′,5′-dione,the title compound was prepared. MS: m/z=376 (M+1).

5′6′-Diamino-3-methyl-spiro[imidazolidine-4,2′-indane]-2,5-dione Step A.(±)-5′-Amino-6′-nitro-3-methyl-spiro[imidazolidine-4,2′-indane]-2,5-dione

To (±)-5′-amino-3-methyl-spiro[imidazolidine-4,2′-indane]-2,5-dione (100mg, 0.432 mmol, described in Intermediate 7) at 0° C. were added 70%HNO₃ (1 mL) followed by conc. H₂SO₄ (1 mL). The resulting mixture wasallowed to warm to ambient temperature and stirred for 18 h, then pouredonto ice and the precipitate was removed by filtration. The aqueousfiltrate was purified by HPLC using a reversed phase C18 column andeluting with a gradient of H₂O:CH₃CN:CF₃CO₂H—90:10:0.1 to 5:95:0.1.Lyophilization provided the title compound. MS: m/z=277 (M+1).

Step B. 5′,6′-Diamino-3-methyl-spiro[imidazolidine-4,2′-indane]2,5-dione

To a solution of(±)-5′-amino-6′-nitro-spiro[imidazolidine-4,2′-indane]-2,5-dione fromStep A (15 mg, 0.054 mmol) in MeOH (5 mL) was added 10% Pd/C (5 mg) andthe reaction mixture was stirred vigorously under hydrogen (ca. 1 atm).After 2 h, the catalyst was filtered off and the filtrate wasconcentrated in vacuo to yield the title compound. MS: m/z=247 (M+1).

(±)-3′-Methyl-2′,5′-dioxo-6,8-dihydrospiro[cyclopenta[g]quinoline-7,4′-imidazolidine]-2-carbaldehyde

Essentially following the procedures described for Intermediate 13, butusing (±)-5′-amino-3-methyl-spiro[imidazolidine-4,2′-indane]-2,5-dione(described in Intermediate 7) in place of(R)-5′-amino-3-methyl-spiro[imidazolidine-4,2′-indane]-2,5-dione, thetitle compound is prepared.

(±)-2-(Chloromethyl)-3′-methyl-6,8-dihydro-2′H,5′H-spiro[cyclopenta[g]quinoline-7,4′-imidazolidine]-2′,5′-dione

Essentially following the procedures described for Intermediate 14, butusing(±)-3′-methyl-2′,5′-dioxo-6,8-dihydrospiro[cyclopenta[g]quinoline-7,4′-imidazolidine]-2-carbaldehyde(described in Intermediate 23) in place of(7R)-3′-methyl-2′,5′-dioxo-6,8-dihydrospiro[cyclopenta[g]quinoline-7,4′-imidazolidine]-2-carbaldehyde,the title compound is prepared.

(±)-3′-Methyl-2′,5′-dioxo-6,8-dihydrospiro[cyclopenta[g]quinoline-7,4′-imidazolidine]-2-carboxylicAcid

A mixture of(±)-2,3′-dimethyl-6,8-dihydro-2′H,5′H-spiro[cyclopenta[g]quinoline-7,4′-imidazolidine]-2′,5′-dione(500 mg, 1.78 mmol, described in Intermediate 23) and selenium dioxide(592 mg, 5.33 mmol) in dioxane (30 mL) and H₂O (3 mL) are heated atreflux for 18 h. The reaction mixture is allowed to cool, filteredthrough a pad of Celite, and the filtrate is concentrated in vacuo togive the title compound.

(2S)-5-Amino-6-(2-aminoethyl)-1,3-dihydrospiro[indene-2,3′-pyrrolo[2,3-b]pyridin]-2′(1′H)-oneStep A. 1-{[2-Trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridine

Sodium hydride (60% dispersion in mineral oil; 16.2 g, 0.404 mol) wasadded in portions over 25 min to a solution of 7-azaindole (39.8 g,0.337 mol) in DMF (200 mL) at 0° C. and the mixture was stirred for 1 h.2-(Trimethylsilyl)ethoxymethyl chloride (71.8 mL, 0.404 mol) was thenadded slowly over 15 min, keeping the temperature of the reactionmixture below 10° C. After 1 h, the reaction was quenched with H₂O (500mL) and the mixture was extracted with CH₂Cl₂ (5×300 mL). The combinedorganic layers were washed with brine, dried over MgSO₄, filtered,concentrated and dried under high vacuum to give the title compound. MS:m/z=249 (M+1).

Step B. 3,3-Dibromo-1-{[2-(trimethylsilyl)ethoxy]methyl}-1,3-dihydro-2H-pyrrolo[2,3-h]pyridin-2-one

A solution of1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridine from StepA (43.1 g, 0.174 mol) in dioxane (300 mL) was added dropwise over 30 minto a suspension of pyridine hydrobromide perbromide (277 g, 0.868 mol)in dioxane (300 mL). The reaction was stirred at ambient temperatureusing an overhead mechanical stirrer. After 60 min, the biphasicreaction mixture was quenched with H₂O (300 mL) and extracted withEtOAc. The aqueous layer was washed with EtOAc (2×300 mL) and thecombined organic layers were washed with H₂O (4×300 mL; the final washwas pH 5-6), then brine (300 mL), then dried over MgSO₄, filtered andconcentrated under reduced pressure. The crude product was immediatelydissolved in CH₂Cl₂ and the solution filtered through a plug of silica,eluting with CH₂Cl₂ until the dark red color had completely eluted fromthe plug. The filtrate was washed with saturated aqueous NaHCO₃ (400mL), then brine (400 mL), dried over MgSO₄ and concentrated in vacuo togive the title compound. MS: m/z=423 (M+1).

Step C.1-{[2-(Trimethylsilyl)ethoxy]methyl}-1,3-dihydro-2H-pyrrolo[2,3-b]pyridin-2-one

Zinc (100 g, 1.54 mol) was added to a solution of3,3-dibromo-1-{[2-(trimethylsilyl)ethoxy]methyl}-1,3-dihydro-2H-pyrrolo[2,3-b]pyridin-2-onefrom Step B (65 g, 0.154 mol) in THF (880 mL) and saturated aqueousammonium chloride (220 mL). After 3 h, the reaction was filtered andconcentrated in vacuo. The residue was partitioned between EtOAc and H₂Owhich resulted in the formation of a white precipitate. Both layers werefiltered through a Celite pad and the layers were separated. The aqueouslayer was washed with EtOAc (2×) and the combined organic layers werewashed with H₂O, dried over MgSO₄, filtered, and concentrated. The crudeproduct was filtered through a plug of silica gel eluting withEtOAc:CH₂Cl₂—1:9 and the eluant was concentrated under reduced pressureto provide the title compound. MS: m/z=265 (M+1).

Step D. (4-Nitro-1,2-phenylene)dimethanol

4-Nitrophthalic acid (40 g, 189.5 mmol) in tetrahydrofuran (500 mL) wasadded dropwise over 1.5 h to a solution of borane-THF complex (1 M, 490mL, 490 mmol), keeping the reaction temperature between 0° C. and 5° C.After the addition, the reaction was allowed to warm slowly to ambienttemperature and stirred for 18 h. Methanol (100 mL) was added carefullyand the precipitated solid dissolved. The mixture was concentrated invacuo to about 500 mL, cooled to 0° C., and 10 N sodium hydroxide wasadded to adjust the pH to 10-11. This mixture was extracted with EtOAc(3×600 mL) and the combined organic layers were washed with brine, driedover Na₂SO₄, filtered, and concentrated in vacuo to give the titlecompound. MS: m/z=207 (M−OH+CH₃CN).

Step E. 1,2-Bis(bromomethyl)-4-nitrobenzene

Phosphorus tribromide (3.9 mL, 41.1 mmol) in ether (50 mL) was addeddropwise over 1.5 h to a solution of (4-nitro-1,2-phenylene)dimethanolfrom Step D (6.85 g, 37.4 mmol) in ether (150 mL). After 18 h, thereaction mixture was cooled to 0° C. and quenched with H₂O (25 mL). Thelayers were separated and the organic layer was washed with H₂O, thensaturated aqueous NaHCO₃, dried over Na₂SO₄, filtered, and concentratedin vacuo to give the title compound as a pale solid. MS: m/z=309 (M+1).

Step F.(±)-5-Nitro-1′-{[2-(trimethylsilyl)ethoxy]methyl}-1,3-dihydrospiro[indene-2,3′-pyrrolo[2,3-b]pyridin]-2′(1′H)-one

To a solution of 1,2-bis(bromomethyl)-4-nitrobenzene from Step E (40.9g, 132 mmol) and1-{[2-(trimethylsilyl)ethoxy]methyl}-1,3-dihydro-2H-pyrrolo[2,3-b]pyridin-2-onefrom Step C (31.5 g, 119 mmol) in DMF (2 L) was added cesium carbonate(129 g, 397 mmol), portionwise, over 5 min. After 18 h, acetic acid (7.6mL) was added and the mixture was concentrated to a volume of about 500mL, then partitioned between EtOAc (1.5 L) and H₂O (1 L). The organiclayer was washed with H₂O (1 L), then brine (500 mL), then dried overNa₂SO₄, filtered, and concentrated in vacuo. The crude product waspurified by silica gel chromatography, eluting with a gradient ofhexane:EtOAc—100:0 to 0:100, to give the title compound. MS: m/z=412(M+1).

Step G.(R)-5-Amino-1′-{[2-(trimethylsily)ethoxy]methyl}-[3-dihydrospiro[indene-2,3′-pyrrolo[2,3-b]pyridin]-2′(1′H)-one

A mixture of 10% Pd/C (3 g) and(±)-5-nitro-1′-{[2-(trimethylsilyl)ethoxy]methyl}-1,3-dihydrospiro[indene-2,3′-pyrrolo[2,3-b]pyridin]-2′(1′H)-onefrom Step F (19.1 g, 46.4 mmol) was stirred vigorously in EtOH (400 mL)under an atmosphere of hydrogen (ca. 1 atm). After 18 h, the mixture wasfiltered through a pad of Celite, washing extensively with MeOH, and thefiltrate was concentrated in vacuo to give the crude racemic compound.The enantiomers were resolved by HPLC, utilizing a Chiralcel OD columnand eluting with MeOH. The first major peak to elute was(S)-5-amino-1′-{[2-(trimethylsilyl)ethoxy]methyl}-1,3-dihydrospiro[indene-2,3′-pyrrolo[2,3-b]pyridin]-2′(1′)-one,and the second major peak to elute was(R)-5-amino-1′-{[2-(trimethylsilyl)ethoxy]methyl}-1,3-dihydrospiro[indene-2,3′-pyrrolo[2,3-b]pyridin]-2′(1′H)-one,the title compound. MS: m/z=382 (M+1).

Step H.(S)-5-Amino-6-nitro-1,3-dihydrospiro[indene-2,3′)pyrrolo[2,3-b]pyridin]-2′(1′H)-one

To a suspension of(R)-5-amino-1′-{[2-(trimethylsilyl)ethoxy]methyl}-1,3-dihydrospiro[indene-2,3′-pyrrolo[2,3-b]pyridin]-2′(1′H)-onefrom Step G (28.7 g, 75.2 mmol) in CH₂Cl₂ (100 mL) was addedtrifluoroacetic anhydride (106 mL, 752 mmol). The mixture was stirredfor 10 min, after which time the aniline had been converted to thecorresponding trifluoroacetanilide. The resulting mixture was cooled inan ice-salt bath and 15.8 M nitric acid (5.0 mL, 79 mmol) was addeddropwise over 15 min, keeping the reaction temperature at 10-12° C.After the addition, the reaction mixture was stirred for 30 min, thenH₂O (12 mL) was carefully added, followed by trifluoroacetic acid (100mL) and CH₂Cl₂ (100 mL). The mixture was allowed to warm to ambienttemperature and stirring was continued for 2 h, followed byconcentration to dryness in vacuo. The residue was dissolved in MeOH(200 mL) and the solution was adjusted to pH 10 by addition of 10 NNaOH. Ethylene diamine (5 mL, 75 mmol) was added and the mixture wasstirred at ambient temperature for 18 h, then diluted with H₂O (200 mL).The resulting solid was isolated by filtration, washed with H₂O, anddried in vacuo to give the title compound. MS: m/z=297 (M+1).

Step I.(2R)-5-Iodo-6-nitro-1,3-dihydrospiro[indene-2,3′-pyrrolo[2,3-b]pyridin]-2′(1′H)-one

To a suspension of(S)-5-amino-6-nitro-1,3-dihydrospiro[indene-2,3′-pyrrolo[2,3-b]pyridin]-2′(1′H)-onefrom Step H (6.14 g, 20.7 mmol) in 3 N hydrochloric acid (50 mL) and THF(20 mL), at −5° C., was added NaNO₂ (1.60 g, 23.2 mmol) in H₂O (10 mL)dropwise at such a rate that the reaction temperature was maintainedbelow 0° C. After a further 15 min, KI (9.2 g, 55 mmol) in H₂O (9 mL)was added dropwise over 30 min, keeping the reaction temperature below0° C. After a further 15 min, the mixture was extracted with CH₂Cl₂(3×300 mL), and the combined organic layers were dried over Na₂SO₄,decanted, and concentrated in vacuo. The crude product was purified bysilica gel chromatography, eluting with a gradient of CH₂Cl₂:MeOH—100:0to 90:10, to give the title compound, which was of sufficient purity foruse in the next step. MS: m/z=408 (M+1).

Step J.(2R)-5-Iodo-6-nitro-1′-{[2-(trimethylsilyl)ethoxy]methyl}-1,3-dihydrospiro[indene-2,3′-pyrrolo[2,3-b]pyridin]-2′(1′H)-one

Sodium hydride (60% dispersion in mineral oil; 525 mg, 13.1 mmol) wasadded to a solution of(2R)-5-iodo-6-nitro-1,3-dihydrospiro[indene-2,3′-pyrrolo[2,3-b]pyridin]-2′(1′H)-onefrom Step I (5.14 g, 12.6 mmol) in DMF (40 mL) at 0° C. and the mixturewas stirred for 5 min. 2-(Trimethylsilyl)ethoxymethyl chloride (2.23 mL,12.6 mmol) was then added dropwise, and the reaction mixture was stirredat 0° C. for 2 h. The reaction was quenched with dilute aqueous NaHCO₃(200 mL) and the mixture was extracted with EtOAc (3×200 mL). Thecombined organic layers were washed with brine, dried over MgSO₄,filtered, and concentrated under reduced pressure. The crude product waspurified by silica gel chromatography, eluting with a gradient ofhexane:EtOAc—100:0 to 0:100, to give the title compound, which was ofsufficient purity for use in the next step. MS: m/z=538 (M+1).

Step K. tert-Butyl((2S)-6-nitro-2′-oxo-1′-{[2-(trimethylsilyl)ethoxy]methyl}-1,1′,2′,3-tetrahydrospiro[indene-2,3′-pyrrolo[2,3-b]pyridin]-5-yl)acetate

To a flask containing(2R)-5-iodo-6-nitro-1′-{[2-(trimethylsilyl)ethoxy]methyl}-1,3-dihydrospiro[indene-2,3′-pyrrolo[2,3-b]pyridin]-2′(1′H)-onefrom Step J (4.02 g, 7.48 mmol), tris(dibenzylideneacetone)dipalladium(349 mg, 0.38 mmol), and1,2,3,4,5-pentaphenyl-1′-(di-tert-butylphosphino)ferrocene (532 mg, 0.75mmol) was added 2-tert-butoxy-2-oxoethylzinc chloride (Rieke, 0.5 M inEt₂O; 15.7 mL, 7.85 mmol) and the resulting solution was heated to 40°C. for 1 h. The reaction was quenched with dilute aqueous NaHCO₃ (100mL) and the mixture was extracted with EtOAc (200 mL). The organic layerwas washed with brine, dried over Na₂SO₄, filtered, and concentratedunder reduced pressure. The crude product was purified by silica gelchromatography, eluting with a gradient of hexane:EtOAc—100:0 to 0:100,to give the title compound, which was of sufficient purity for use inthe next step. MS: m/z=526 (M+1).

Step L.[(2S)-6-Nitro-2′-oxo-1,1′,2′,3-tetrahydrospiro[indene-2,3′-pyrrolo[2,3-b]pyridin]-5-yl]aceticAcid

A solution of tert-butyl((2S)-6-nitro-2′-oxo-1′-{[2-(trimethylsilyl)ethoxy]methyl}-1,1′,2′,3-tetrahydrospiro[indene-2,3′-pyrrolo[2,3-b]pyridin]-5-yl)acetatefrom Step K (2.01 g, 3.83 mmol) in MeOH (25 mL) was saturated with HCl(g) and stood at ambient temperature for 18 h. The mixture wasconcentrated to dryness in vacuo, then redissolved in MeOH (25 mL). Thisstirred solution was adjusted to pH 10 with 10 N NaOH and ethylenediamine (0.26 mL, 3.83 mmol) was added. The resulting mixture wasstirred for 3 h, then concentrated to dryness in vacuo. The residue wasdissolved in THF (25 mL) and 1 N NaOH (25 mL, 25 mmol) was added. Themixture was stirred at ambient temperature for 18 h, then the THF wasremoved under reduced pressure. The residual mixture was partitionedbetween saturated aqueous NaHCO₃ (50 mL) and EtOAc (100 mL). The organiclayer was discarded and the aqueous layer was adjusted to pH 2 withaqueous HCl, then extracted with EtOAc (3×200 mL). The combined organiclayers were dried over Na₂SO₄, filtered, and concentrated under reducedpressure to give the title compound. MS: m/z=340 (M+1).

Step M.(21)-5-(2-Hydroxyethyl)-6-nitro-1,3-dihydrospiro[indene-2,3′-pyrrolo[2,3-b]pyridin]-2′(1)-one

To a stirred solution of[(2S)-6-nitro-2′-oxo-1,1′,2′,3-tetrahydrospiro[indene-2,3′-pyrrolo[2,3-b]pyridin]-5-yl]aceticacid from Step L (753 mg, 2.22 mmol) in THF (15 mL), at −78° C., wasadded borane (1 M in TH; 9.1 mL, 9.1 mmol) dropwise. After 5 min, themixture was warmed to 0° C. and stirring was continued at thistemperature for 3 h. The reaction was quenched carefully with 1 N HCland stirring was continued at ambient temperature. The mixture wasadjusted to pH 8 with saturated aqueous NaHCO₃ and extracted with EtOAc(2×100 mL). The combined organic layers were dried over Na₂SO₄,filtered, and concentrated under reduced pressure. The crude product waspurified by silica gel chromatography, eluting with a gradient ofCH₂Cl₂:MeOH—100:0 to 80:20, to give the title compound. MS: m/z=326(M+1).

Step N.(2S)-5-(2-Azidoethyl)-6-nitro-1,3-dihydrospiro[indene-23′-pyrrolo[2,3′-b]pyridin]-2′(1′H)-one

To a stirred solution of(2S)-5-(2-hydroxyethyl)-6-nitro-1,3-dihydrospiro[indene-2,3′-pyrrolo[2,3-b]pyridin]-2′(1′H)-onefrom Step M (174 mg, 0.54 mmol) in DMF (4 mL) were added diphenylphosphoryl azide (177 mg, 0.64 mmol) and DBU (0.096 mL, 0.64 mmol). Themixture was heated at 100° C. for 6 h, then quenched with H₂O (20 mL)and extracted with EtOAc (50 mL). The organic layer was dried overNa₂SO₄, filtered, and concentrated under reduced pressure. The crudeproduct was purified by silica gel chromatography, eluting with agradient of CH₂Cl₂:MeOH—100:0 to 80:20, to give the title compound. MS:m/z=351 (M−1).

Step O.(2S)-5-Amino-6-(2-aminoethyl)-1,3-dihydrospiro[indene-2,3′-pyrrolo[2,3-b]pyridin]-2′(1′H)-one

To a solution of(2S)-5-(2-azidoethyl)-6-nitro-1,3-dihydrospiro[indene-2,3′-pyrrolo[2,3-b]pyridin]-2′(1H)-onefrom Step N (236 mg, 0.67 mmol) in EtOH (15 mL) was added 10% Pd/C (172mg). The reaction mixture was stirred under a hydrogen atmosphere (ca. 1atm) for 5 h, then filtered through a Celite pad, washing with MeOH, andthe filtrate was concentrated under reduced pressure to give the titlecompound. MS: m/z=295 (M+1).

(±)-5′-Amino-6′-(2-aminoethyl)-3-methyl-1′,3′-dihydro-2H5H-spiro[imidazolidine-4,2′-indene]-2,5-dione

Essentially following the procedures described for Intermediate 26, butusing (±)-5′-amino-6′-nitro-spiro[imidazolidine-4,2′-indane]-2,5-dione(described in Intermediate 22) in place of(S)-5-amino-6-nitro-1,3-dihydrospiro[indene-2,3′-pyrrolo[2,3-b]pyridin]-2′(1′H)-one,the title compound is prepared.

6-Methyl-4H-imidazo[1,5,4-de]quinoxaline-2,5(1H,6H-dione Step A.N-(2-Amino-3-nitrophenyl)-4-methylbenzenesulfonamide

A stirred mixture of 3-nitro-1,2-phenylenediamine (1.00 g, 6.53 mmol)and p-toluenesulfonyl chloride (1.25 g, 6.53 mmol) in pyridine (50 ml)was heated at reflux for 1 h, then concentrated to dryness in vacuo togive the title compound in sufficient purity for use in the next step.MS: m/z=308 (M+1).

Step B.1-[(4-Methylphenyl)sulfonyl]-4-nitro-1,3-dihydro-2H-benzimidazol-2-one

To a stirred solution ofN-(2-amino-3-nitrophenyl)-4-methylbenzenesulfonamide from Step A (2.00g, 6.51 mmol) in CH₃CN (100 mL) was added triphosgene (966 mg, 3.25mmol) and the mixture was stirred at ambient temperature for 30 min. Theprecipitate was isolated by filtration and dried in vacuo to give thetitle compound. MS: m/z=334 (M+1).

Step C. Methyl{3-[(4-methylphenyl)sulfonyl]-7-nitro-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl}acetate

To a stirred solution of1-[(4-methylphenyl)sulfonyl]-4-nitro-1,3-dihydro-2H-benzimidazol-2-onefrom Step B (500 mg, 1.50 mmol) in DMF (50 mL) was added potassiumcarbonate (207 mg, 1.50 mmol) and the resulting mixture was stirred atambient temperature for 10 min. Methyl bromoacetate (252 mg, 1.65 mmol)was added dropwise and the reaction mixture was stirred for 1 h, thenpoured into H₂O (50 mL). The resulting precipitate was isolated byfiltration, washed with H₂O, and dried in vacuo to give the titlecompound. MS: m/z=406 (M+1).

Step D.1-[(4-Methylphenyl)sulfonyl]-4H-imidazo[1,5,4-de]quinoxaline-2,5(1H,6H)-dione

A mixture of methyl{3-[(4-methylphenyl)sulfonyl]-7-nitro-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl}acetatefrom Step C (1.00 g, 2.47 mmol) and 10% Pd/C (100 mg) was stirredvigorously in EtOAc (100 mL) under an atmosphere of hydrogen (ca. 1atm). After 4 h, the mixture was filtered through a pad of Celite,washing with EtOAc (300 mL). To the filtrate was added AcOH (2 mL) andthis solution was heated at 80° C. for 1 h, then concentrated in vacuoto give the title compound. MS: m/z=344 (M+1).

Step E.1-[(4-Methylphenyl)sulfonyl]-6-methyl-4H-imidazo[1,5,4-de]quinoxaline-2,5(1H,6H-dione

To a stirred solution of1-[(4-methylphenyl)sulfonyl]-4H-imidazo[1,5,4-de]quinoxaline-2,5(1H,6H)-dionefrom Step D (1.16 g, 3.38 mmol) in DMF (40 mL) was added potassiumcarbonate (467 mg, 3.38 mmol) and the resulting mixture was stirred atambient temperature for 10 min. Iodomethane (480 mg, 3.38 mmol) wasadded dropwise and the reaction mixture was stirred for 18 h, thenpoured into H₂O (50 mL). The resulting precipitate was isolated byfiltration, washed with H₂O, and dried in vacuo to give the titlecompound. MS: m/z=358 (M+1).

Step F. 6-Methyl-4H-imidazo[1,5,4-de]quinoxaline-2,5(1H,6H)-dione

A solution of1-[(4-methylphenyl)sulfonyl]-6-methyl-4H-imidazo[1,5,4-de]quinoxaline-2,5(1H,6H)-dione(600 mg, 1.68 mmol) in conc. H₂SO₄ (3 mL) was heated at 50° C. for 30min, then poured into H₂O at 0° C. (25 mL). The resulting precipitatewas isolated by filtration, washed with H₂O, and dried in vacuo to givethe title compound. MS: m/z=204 (M+1).

2a-(2-Pyrrolidin-1-ylethyl)-1,2,2a,5-tetrahydropyrrolo[4,3,2-de]quinolin-4(3H)-one,Enantiomer A Step A. tert-Butyl2a-(2-ethoxy-2-oxoethyl)-4-oxo-2a,3,4,5-tetrahydropyrrolo[4,3,2-de]quinolin-1(2H)-carboxylate,Enantiomer A

To a stirred solution of ethyl(4-oxo-1,2,4,5-tetrahydropyrrolo[4,3,2-de]quinolin-2a(3H)-yl)acetate,enantiomer A, (158 mg, 0.607 mmol, described in Intermediate 20) andtriethylamine (0.127 mL, 0.91 mmol) in CH₂Cl₂ (5 mL) was addeddi-tert-butyl dicarbonate (199 mg, 0.91 mmol). The mixture was stirredat ambient temperature for 19 h, then additional di-tert-butyldicarbonate (100 mg, 0.46 mmol) and triethylamine (0.060 mL, 0.43 mmol)were added and stirring was continued for 72 h. The reaction mixture wasquenched with saturated aqueous NaHCO₃ (10 mL) and extracted with CH₂Cl₂(3×20 mL). The combined organic extracts were dried over Na₂SO₄,filtered, and concentrated in vacuo to give the title compound insufficient purity for use in the next step. MS: m/z=305 (M—C₄H₇).

Step B. tert-Butyl4-oxo-2a-(2-oxoethyl)-2a,3,4,5-tetrahydropyrrolo[4,3,2-de]quinolin-1(2H)-carboxylate,Enantiomer A

To a stirred solution of tert-butyl2a-(2-ethoxy-2-oxoethyl)-4-oxo-2a,3,4,5-tetrahydropyrrolo[4,3,2-de]quinolin-1(2H)-carboxylate,enantiomer A, from Step A (219 mg, 0.607 mmol) in CH₂Cl₂ (5 mL) at −78°C. was added DIBAL-H (1 M in CH₂Cl₂, 0.8 mL, 0.8 mmol) dropwise. After 1h, DIBAL-H (1 M in CH₂Cl₂, 0.54 mL, 0.54 mmol) was added dropwise, andafter an additional 1 h, more DIBAL-H (1 M in CH₂Cl₂, 0.65 mL, 0.65mmol) was added dropwise. The mixture was stirred at −78° C. for 1 h,then quenched by addition of cold MeOH (1 mL), then acetone (1 mL), thensaturated aqueous potassium sodium tartrate (10 mL). The mixture wasallowed to warm to ambient temperature and was extracted with CH₂Cl₂(3×20 mL). The combined organic extracts were washed with brine (10 mL),dried over Na₂SO₄, filtered, and concentrated in vacuo to give the titlecompound in sufficient purity for use in the next step. MS: m/z=317(M+1).

Step C.2a-(2-Pyrrolidin-1-ylethyl)-1,2,2a,5-tetrahydropyrrolo[4,3,2-de]quinolin-4(3H)-one,Enantiomer A

To a stirred solution of tert-butyl4-oxo-2a-(2-oxoethyl)-2a,3,4,5-tetrahydropyrrolo[4,3,2-de]quinolin-1(2H)-carboxylate,enantiomer A, from Step B (100 mg, 0.316 mmol), pyrrolidine (67 mg,0.948 mmol), and AcOH (0.09 mL, 1.58 mmol) in DCE (1 mL) was addedsodium triacetoxyborohydride (80 mg, 0.38 mmol) and the mixture wasstirred for 18 h. To the resulting mixture was added TFA (1 mL) andstirring was continued for 4 h. The mixture was concentrated in vacuoand purified by HPLC using a reversed phase C18 column and eluting witha gradient of H₂O:CH₃CN:CF₃CO₂H —90:10:0.1 to 5:95:0.1. Lyophilizationprovided the title compound as the trifluoroacetate salt. MS: m/z=272(M+1).

2a-Ethyl-1,2,2a,5-tetrahydropyrrolo[4,3,2-de]quinolin-4(3H)-one,Enantiomer B Step A. (±)-Ethyl(3-ethyl-4-nitro-2-oxo-2,3-dihydro-1H-indol-3-yl)acetate

Essentially following the procedures described for Intermediate 16, butusing iodoethane in place of iodomethane, the title compound wasprepared. MS: m/z=293 (M+1).

2a-Ethyl-1,2,2a,5-tetrahydropyrrolo[4,3,2-de]quinolin-4(3)-one,Enantiomer B

Essentially following the procedures described for Intermediate 19, butusing (±)-ethyl (3-ethyl-4-nitro-2-oxo-2,3-dihydro-1H-indol-3-yl)acetatein place of (±)-ethyl(3-methyl-4-nitro-2-oxo-2,3-dihydro-1H-indol-3-yl)acetate, the racemictitle compound was prepared. The enantiomers were resolved by HPLC,utilizing a ChiralPak AS column and eluting withhexane:EtOH:Et₂NH—20:80:0.1. The first major peak to elute was2a-ethyl-1,2,2a,5-tetrahydropyrrolo[4,3,2-de]quinolin-4(3H)-one,enantiomer A, and the second major peak to elute was2a-ethyl-1,2,2a,5-tetrahydropyrrolo[4,3,2-de]quinolin-4(3H)-one,enantiomer B, the title compound. MS: m/z=203 (M+1).

Sodium (2,5-dioxo-5,6-dihydro-4H-imidazo[1,5,4-de]quinoxalin-1(2R)-yl)acetate Step A. 4-Nitro-1,3-dihydro-2H-benzimidazol-2-one

Triphosgene (56 g, 188.8 mol) was added portionwise over 15 min to asolution of 3-nitro-1,2-phenylenediamine (25.5 g, 167 mol) in CH₃CN (400mL) at 0° C. and the mixture was allowed to warm to ambient temperatureafter 30 min. The reaction was concentrated in vacuo, diluted withtoluene (100 mL) and the solid precipitate was collected by filtrationto give the title compound. MS: m/z=180 (M+1).

Step B. Dimethyl 2,2′-(4-nitro-2-oxo-1H-benzimidazole-1,3-diyl)diacetate

Cesium carbonate (3.6 g, 11.1 mmol) was added to a solution of4-nitro-1,3-dihydro-2H-benzimidazol-2-one from Step A (990 mg, 5.5 mmol)and methyl bromoacetate (1.05 mL, 11.1 mmol) in DMF (25 mL). After 1.5h, the reaction was quenched with H₂O and the solid precipitate wascollected by filtration to give the title compound. MS: m/z=324 (M+1).

Step C. Methyl(2,5-dioxo-5,6-dihydro-4H-imidazo[1,5,4-de]quinoxalin-1(2H)-yl)acetate

A mixture of dimethyl2,2′-(4-nitro-2-oxo-1H-benzimidazole-1,3-diyl)diacetate from Step B (270mg, 0.84 mmol) and 10% Pd/C (50 mg) in MeOH (10 mL) was stirred under anatmosphere of hydrogen (ca. 1 atm). After 2 h, the reaction was filteredthrough a Celite pad and concentrated in vacuo. The crude solid wasdissolved in toluene (3 mL) and p-toluenesulfonic acid monohydrate (2mg, 0.011 mmol) was added. The mixture was heated at reflux for 30 minand then concentrated in vacuo to give the title compound. MS: m/z=262(M+1).

Step D. Sodium(2,5-dioxo-5,6-dihydro-4H-imidazo[1,5,4-de]quinoxalin-1(2H)-yl)acetate

To a solution of methyl(2,5-dioxo-5,6-dihydro-4H-imidazo[1,5,4-de]quinoxalin-1(2H)-yl)acetatefrom Step C (367 mg, 1.40 mmol) in MeOH (40 mL) and CH₃CN (5 mL) wasadded 1.0 N sodium hydroxide (2.82 mL, 2.82 mmol) and the reactionmixture was stirred at ambient temperature for 18 h. The mixture wasneutralized with 1 N aqueous HCl and concentrated in vacuo to give thetitle compound. MS: m/z=248 (M+1).

(2,7-Dioxo-5,6,7,8-tetrahydro-4H-imidazo[1,5,4-fg][1,6]benzodiazocin-1(2H)-yl)aceticAcid Step A. tert-Butyl(4-nitro-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl)acetate

Cesium carbonate (1.75 g, 5.4 mmol) was added to a solution of4-nitro-1,3-dihydro-2H-benzimidazol-2-one (800 mg, 4.5 mmol, describedin Intermediate 31) and tert-butyl bromoacetate (0.791 mL, 5.4 mmol) inDMF (15 mL). After 18 h, the reaction was quenched with H₂O (100 mL) andthe solid precipitate was collected by filtration. The crude product waspurified by silica gel chromatography, eluting with CH₂Cl₂:MeOH—95:5, togive the title compound. MS: m/z=294 (M+1).

Step B. Methyl4-[3-(2-tert-butoxy-2-oxoethyl)-7-nitro-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl]butanoate

Sodium hydride (26.7 mg of a 60% dispersion in mineral oil, 0.66 mmol)was added to a solution of tert-butyl(4-nitro-2-oxo-2,3-dihydro-11H-benzimidazol-1-yl)acetate from Step A (96mg, 0.327 mmol) in DMF (5 mL). After 10 min, methyl 4-bromobutyrate (178mg, 0.98 mmol) was added and the reaction was stirred at roomtemperature for 18 h. The mixture was quenched with H₂O and extractedwith EtOAc. The organic extract was washed with brine, dried overNa₂SO₄, filtered, and concentrated in vacuo. The residue was purified byHPLC using a reversed phase C18 column and eluting with a gradient ofH₂O:CH₃CN:CF₃CO₂H—90:10:0.1 to 5:95:0.1. Lyophilization provided thetitle compound. MS: m/z=394 (M+1).

Step C. Methyl4-[7-amino-3-(2-tert-butoxy-2-oxoethyl)-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl]butanoate

A mixture of methyl4-[3-(2-tert-butoxy-2-oxoethyl)-7-nitro-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl]butanoatefrom Step B (129 mg, 0.33 mmol) and 10% Pd/C (40 mg) in EtOH (30 mL) andEtOAc (15 mL) was stirred under an atmosphere of hydrogen (ca. 1 atm).After 1 h, the reaction was filtered through a Celite pad andconcentrated in vacuo to give the title compound. MS: m/z=364 (M+1).

Step D. tert-Butyl(2,7-dioxo-5,6,7,8-tetrahydro-4H-imidazo[1,5,4-fg][1,6]benzodiazocin-1(2H)-yl)acetate

To a solution of methyl4-[7-amino-3-(2-tert-butoxy-2-oxoethyl)-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl]butanoatefrom Step C (119 mg, 0.327 mmol) in toluene (5 mL) was addedp-toluenesulfonic acid monohydrate (2 mg, 0.011 mmol) and the mixturewas heated at reflux. After 3 h, the reaction mixture was allowed tocool to ambient temperature and the mixture was concentrated in vacuo togive the title compound. MS: m/z=332 (M+1).

Step E.(2,7-Dioxo-5,6,7,8-tetrahydro-4H-imidazo[1,5,4-fg][1,6]-benzodiazocin-1(2H)-yl)aceticAcid

To a solution of tert-butyl(2,7-dioxo-5,6,7,8-tetrahydro-4H-imidazo[1,5,4-fg][1,6]benzodiazocin-1(2H)-yl)acetatefrom Step D (15 mg, 0.045 mmol) in CH₂Cl₂ (3 mL) was added TFA (1 mL).After 2 h, the mixture was concentrated under reduced pressure to givethe title compound. MS: m/z=276 (M+1).

(8-Methyl-2,7-dioxo-5,6,7,8-tetrahydro-4H-imidazo[1,5,4-fg][1,6]benzodiazocin-1(2H)-yl)aceticAcid Step A. tert-Butyl(8-methyl-2,7-dioxo-5,6,7,8-tetrahydro-4H-imidazo[1,5,4-fg][1,6]-benzodiazocin-1(2H)-yl)acetate

Cesium carbonate (214 mg, 0.66 mmol) and iodomethane (93 mg, 0.66 mmol)were added to a solution of tert-butyl(2,7-dioxo-5,6,7,8-tetrahydro-4H-imidazo[1,5,4-fg][1,6]benzodiazocin-1(2H)-yl)acetate(109 mg, 0.33 mmol, described in Intermediate 32) in DMF (5 mL). After18 h, the mixture was purified directly by HPLC using a reversed phaseC18 column and eluting with a gradient of H₂O:CH₃CN:CF₃CO₂H—90:10:0.1 to5:95:0.1. Lyophilization provided the title compound. MS: m/z=346 (M+1).

Step B.(8-Methyl-2,7-dioxo-5,6,7,8-tetrahydro-4H-imidazo[1,5,4-fg][1,6]benzodiazocin-1(2H)-yl)aceticAcid

To a solution of tert-butyl(8-methyl-2,7-dioxo-5,6,7,8-tetrahydro-4H-imidazo[1,5,4-fg][1,6]benzodiazocin-1(2H)-yl)acetatefrom Step A (45 mg, 0.13 mmol) in CH₂Cl₂ (6 mL) was added TFA (2 mL).After 2 h, the mixture was concentrated under reduced pressure to givethe title compound. MS: m/z=290 (M+1).

Lithium(7-methyl-4-oxo-4,5-dihydropyrrolo[4,312-de]quinolin-1(3H)-yl)acetateStep A. 2,5-Dimethyl-3-nitroaniline

To a stirred solution of p-xylene (10.4 g, 97.9 mmol) in concentratedsulfuric acid (20 mL), cooled in an ice bath, was added 90% nitric acid(12.4 mL, 264 mmol) dropwise over 50 min. The resulting mixture washeated to 80° C. for 2 h, then poured onto ice and extracted with CH₂Cl₂(2×400 mL). The combined organic extracts were washed with saturatedaqueous NaHCO₃, then brine, then dried over Na₂SO₄, filtered, andconcentrated in vacuo. The crude product was partially purified bysilica gel chromatography, eluting with a gradient of hexane:EtOAc—90:10to 60:40. The resulting solid was recrystallized from CH₂Cl₂ to yield2,5-dimethyl-1,3-dinitrobenzene as a white solid.2,5-Dimethyl-1,3-dinitrobenzene (3.68 g, 18.8 mmol) was dissolved inAcOH (35 mL) and iron powder (1.95 g, 34.9 mmol) was added. The mixturewas heated to 110° C. for 3 h, then filtered through a pad of Celite,washing with EtOAc and H₂O. The filtrate was concentrated in vacuo toremove most of the solvent and the residue was partitioned betweensaturated aqueous NaHCO₃ (200 mL) and EtOAc (200 mL). The organic layerwas washed with brine, then dried over Na₂SO₄, filtered, andconcentrated in vacuo. The crude product was purified by silica gelchromatography, eluting with a gradient of hexane:EtOAc—100:0 to 60:40,to give the title compound. MS: m/z=167 (M+1).

Step B. 6-Methyl-4-nitro-1H-indole

A solution of 2,5-dimethyl-3-nitroaniline from Step A (1.21 g, 7.26mmol) and p-toluenesulfonic acid monohydrate (2 mg, 0.011 mmol) infreshly distilled triethyl orthoformate (1.65 mL, 9.92 mmol) was heatedat 120° C. for 45 min in a distillation apparatus, and about 0.4 mL ofEtOH distilled over. Vacuum distillation of the residual solutionyielded ethyl 2,5-dimethyl-3-nitrophenylimidoformate (b.p.=146° C., ca.2 mm Hg) as a pale yellow solid. To a solution of diethyl oxalate (868mg, 5.94 mmol) in DMF (2 mL), at 0° C., was added potassium ethoxide(435 mg, 5.17 mmol) and the resulting solution was added to a solutionof ethyl 2,5-dimethyl-3-nitrophenylimidoformate (880 mg, 3.96 mmol) inDMSO (3 mL). The reaction mixture was heated at 40° C. for 1 h thanquenched with H₂O (30 mL) and extracted with EtOAc (2×50 mL). Thecombined organic layers were washed with brine, then dried over Na₂SO₄,filtered, and concentrated in vacuo. The crude product was purified bysilica gel chromatography, eluting with a gradient of hexane:EtOAc—100:0to 0:100, to give the title compound. MS: m/z=177 (M+1).

Lithium(7-methyl-4-oxo-4,5-dihydropyrrolo[4,3,2-de]quinolin-1(3H)-yl)acetate

Essentially following the procedures described for Intermediate 46, butusing 6-methyl-4-nitro-1H-indole in place of 4-nitroindole, the titlecompound was prepared. MS: m/z=245 (M+1).

Lithium (7-methyl-4-oxo-2a,3,4,5-tetrahydropyrrolo[4,3,2-de]quinolin-1(2H)-yl)acetate, Enantiomer B

Essentially following the procedures described for Intermediate 47, butusing 6-methyl-4-nitro-1H-indole (described in Intermediate 34) in placeof 4-nitroindole, the title compound was prepared. MS: m/z=247 (M+1).

Lithium(6-chloro-4-oxo-4,5-dihydropyrrolo[4,3,2-de]quinolin-1(3H)-yl)acetateStep A. tert-Butyl [4-amino-3-(cyanomethyl)-1H-indol-1-yl]acetate

A mixture of tert-butyl [3-(cyanomethyl)-4-nitro-1H-indol-1-yl]acetate(700 mg, 2.22 mmol, described in Intermediate 46) and 10% Pd/C (65 mg)in EtOH (20 mL) was stirred under an atmosphere of hydrogen (ca. 1 atm).After 4 h, the reaction was filtered through a Celite pad andconcentrated in vacuo to give the title compound. MS: m/z=286 (M+1).

Step B. tert-Butyl[4-amino-5-chloro-3-(cyanomethyl-1H-indol-1-yl]acetate

To a solution of tert-butyl[4-amino-3-(cyanomethyl)-1H-indol-1-yl]acetate from Step A (150 mg,0.526 mmol) in CH₂Cl₂ (5 mL) was added N-chlorosuccinimide (70 mg, 0.526mmol). The reaction mixture was stirred at ambient temperature for 30min, then partitioned between saturated aqueous NaHCO₃ (5 mL) and CHCl₃(15 mL). The aqueous phase was extracted further with CHCl₃ (15 mL) andthe combined organic extracts were dried over Na₂SO₄, filtered, andconcentrated in vacuo to give the title compound, which was ofsufficient purity for use in the next step. MS: m/z=320 (M+1).

Lithium(6-chloro-4-oxo-4,5-dihydropyrrolo[4,3,2-de]quinolin-1(3H)-yl)acetate

Essentially following the procedures described for Intermediate 46, butusing tert-butyl [4-amino-5-chloro-3-(cyanomethyl)-1H-indol-1-yl]acetatein place of tert-butyl [3-(cyanomethyl)-4-nitro-1H-indol-1-yl]acetate,the title compound was prepared. MS: m/z=283 (M+1).

Lithium (4-oxo-4,5-dihydropyrrolo[2,3,4-ij]isoquinolin-1(3H)-yl)acetateStep A. 4-Bromo-1-(phenylsulfonyl)-1H-indole

To a solution of 4-bromoindole (1.00 g, 5.10 mmol) in DMF (50 mL) atambient temperature was added sodium hydride (220 mg of a 60% dispersionin mineral oil, 5.50 mmol). The reaction mixture was stirred for 5 min,then benzenesulfonyl chloride (901 mg, 5.10 mmol) was added and stirringwas continued for 15 min. The reaction was quenched with saturatedaqueous NaHCO₃ (50 mL) and extracted with CHCl₃ (2×75 mL). The combinedorganic extracts were dried over Na₂SO₄, filtered, and concentrated invacuo. The crude product was purified by silica gel chromatography,eluting with a gradient of hexane:EtOAc—100:0 to 90:10, to give thetitle compound. MS: m/z=336 (M+1).

Step B. tert-Butyl [1-(phenylsulfonyl)-1H-indol-4-yl]acetate

To a mixture of 1,3-bis(2,6-diisopropylphenyl)-4,5-dihydroimidazoliumtetrafluoroborate (94 mg, 0.196 mmol),tris(dibenzylideneacetone)dipalladium (180 mg, 0.196 mmol), and lithiumbis(trimethylsilyl)amide (1.37 M in t-BuOMe, 11.0 mL, 15.1 mmol) wereadded 4-bromo-1-(phenylsulfonyl)-1H-indole from Step A (2.20 g, 6.54mmol), tert-butyl acetate (988 mg, 8.51 mmol), and toluene (15 mL). Theresulting mixture was stirred at ambient temperature for 18 h thenpartitioned between Et₂O (100 mL) and saturated aqueous NH₄Cl (30 mL).The organic layer was washed with brine, then dried over Na₂SO₄,filtered, and concentrated in vacuo. The crude product was purified bysilica gel chromatography, eluting with a gradient of hexane:EtOAc—100:0to 85:15, to give the title compound. MS: m/z=316 (M—C₄H₇).

Step C. tert-Butyl [3-nitro-1-(phenylsulfonyl)-1H-indol-4-yl]acetate

To acetic anhydride (5 mL) at 0° C. was added 90% nitric acid (0.183 mL,3.90 mmol) and the resulting mixture was aged for 10 min, then addeddropwise to a solution of tert-butyl[1-(phenylsulfonyl)-1H-indol-4-yl]acetate from Step B (1.00 g, 2.69mmol) in acetic anhydride (5 mL) at −78° C. The reaction mixture wasstirred at −78° C. for 6 h, then aged at −20° C. for 16 h, then quenchedwith H₂O and extracted with EtOAc (2×10 mL). The combined organicextracts were dried over Na₂SO₄, filtered, and concentrated in vacuo.The crude product was purified by silica gel chromatography, elutingwith a gradient of hexane:EtOAc—100:0 to 70:30, to give the titlecompound. MS: m/z=361 (M—C₄H₇).

Step D. tert-Butyl [3-nitro-1H-indol-4-yl]acetate

To a solution of tert-butyl[3-nitro-1-(phenylsulfonyl)-1H-indol-4-yl]acetate from Step C (730 mg,1.75 mmol) in THF (5 mL) was added tetrabutylammonium fluoride (1.0 M inTHF, 5.25 mL, 5.25 mmol) and the reaction mixture was stirred at ambienttemperature for 10 min, then concentrated in vacuo. The residue waspartitioned between saturated aqueous NaHCO₃ (5 mL) and extracted withCHCl₃ (15 mL). The organic extract was dried over Na₂SO₄, filtered, andconcentrated in vacuo. The crude product was purified by silica gelchromatography, eluting with a gradient of CHCl₃:EtOAc 90:10 to 50:50,to give the title compound. MS: m/z=221 (M—C₄H₇).

Step E. tert-Butyl[1-(2-ethoxy-2-oxoethyl)-3-nitro-1H-indol-4-yl]acetate

To a solution of tert-butyl [3-nitro-1H-indol-4-yl]acetate from Step D(385 mg, 1.39 mmol) in DMF (5 mL) at ambient temperature was addedsodium hydride (60 mg of a 60% dispersion in mineral oil, 1.50 mmol).The reaction mixture was stirred for 5 min, then ethyl bromoacetate (256mg, 1.53 mmol) was added and stirring was continued for 10 min. Thereaction was quenched with saturated aqueous NaHCO₃ (5 mL) and extractedwith CHCl₃ (2×25 mL). The combined organic extracts were dried overNa₂SO₄, filtered, and concentrated in vacuo. The crude product waspurified by silica gel chromatography, eluting with a gradient ofhexane:EtOAc—90:10 to 40:60, to give the title compound. MS: m/z=307(M—C₄H₇).

Step F. [1-(2-Ethoxy-2-oxoethyl)-3-nitro-1H-indol-4-yl]acetic Acid

To a solution of tert-butyl[1-(2-ethoxy-2-oxoethyl)-3-nitro-1H-indol-4-yl]acetate from Step E (300mg, 0.828 mmol) in CH₂Cl₂ (1 mL) was added TFA (0.63 mL, 8.28 mmol). Themixture was stirred at ambient temperature for 1 h then concentrated invacuo to give the title compound. MS: m/z=307 (M+1).

Step G. Ethyl(4-oxo-4,5-dihydropyrrolo[2,3,4-ij]isoquinolin-1(3H)-yl)acetate

To a solution of [1-(2-ethoxy-2-oxoethyl)-3-nitro-1H-indol-4-yl]aceticacid from Step F (250 mg, 0.816 mmol) in AcOH (18 mL) and H₂O (2 mL) wasadded iron powder (456 mg, 8.16 mmol) and the reaction mixture washeated at 80° C. for 18 h. The mixture was concentrated in vacuo toremove most of the solvent and the residue was partitioned betweensaturated aqueous NaHCO₃ (5 mL) and EtOAc (25 mL). The organic layer waswashed with brine, then dried over Na₂SO₄, filtered, and concentrated invacuo to give the title compound, which was of sufficient purity for usein the next step. MS: m/z=259 (M+1).

Step H. Lithium(4-oxo-4,5-dihydropyrrolo[2,3,4-ij]isoquinolin-[(3H)-yl)acetate

To a solution of ethyl(4-oxo-4,5-dihydropyrrolo[2,3,4-#]isoquinolin-1(3H)-yl)acetate from StepG (200 mg, 0.77 mmol) in THF (1 mL), EtOH (1 mL) and H₂O (1 mL) wasadded 1.0 N lithium hydroxide (0.85 mL, 0.85 mmol). After 15 min, 1 Naqueous HCl was added to adjust the solution to pH 7 and the mixture wasconcentrated in vacuo to give the title compound. MS: m/z=231 (M+1).

(7-Methyl-6-oxo-2a,3,4,5,6,7-hexahydroazocino[4,3,2-cd]indol-1(2H)-yl)aceticAcid, Enantiomer A Step A. Ethyl4-(4-nitro-1H-indol-3-yl)-4-oxobutanoate

To a stirred solution of 4-nitroindole (2.00 g, 12.3 mmol) in CH₂Cl₂ (60mL) at 0° C. was added dimethylaluminum chloride (1 M in hexanes, 14.8mL, 14.8 mmol) and the mixture was stirred for 30 min. Ethyl4-chloro-4-oxobutyrate (2.44 g, 14.8 mmol) was added dropwise and theresulting mixture was allowed to warm slowly to ambient temperature andstirred for 18 h. The reaction mixture was carefully quenched with 10%aqueous citric acid (150 mL) and extracted with CH₂Cl₂ (3×150 mL). Thecombined organic extracts were dried over Na₂SO₄, filtered, andconcentrated in vacuo. The residue was partially purified by silica gelchromatography, eluting with a gradient of CH₂Cl₂:EtOAc—100:0 to 65:35,and the resulting crude product was recrystallized from CH₂Cl₂:MeOH togive the title compound. MS: m/z=291 (M+1).

Step B. Ethyl 4-(4-nitro-2,3-dihydro-1H-indol-3-yl)butanoate

Triethylsilane (11 mL, 68 mmol) was added to a solution of ethyl4-(4-nitro-1H-indol-3-yl)-4-oxobutanoate from Step A (960 mg, 3.31 mmol)in TFA (15 mL). After 3 h, the reaction mixture was concentrated invacuo and the residue was purified by silica gel chromatography, elutingwith a gradient of CHCl₃:MeOH—100:0 to 94:6, to give the title compound.MS: m/z=279 (M+1).

Step C. Ethyl4-[1-(2-tert-butoxy-2-oxoethyl)-4-nitro-2,3-dihydro-1H-indol-3-yl]butanoate

To a solution of ethyl 4-(4-nitro-2,3-dihydro-1H-indol-3-yl)butanoatefrom Step B (1.10 g, 3.95 mmol), sodium carbonate (628 mg, 5.93 mmol),and potassium iodide (131 mg, 0.79 mmol) in acetone (10 mL) was addedtert-butyl bromoacetate (17.5 mL, 119 mmol). The mixture was heated atreflux for 18 h, then cooled to ambient temperature and concentrated invacuo. The residue was partitioned between H₂O (30 mL) and EtOAc (2×60mL) and the organic extracts were dried over Na₂SO₄, filtered, andconcentrated in vacuo. The crude product was purified by silica gelchromatography, eluting with a gradient of hexane:EtOAc—90:10 to 65:35,to give the title compound. MS: m/z=365 (M+1).

Step D. Ethyl4-[4-amino-1-(2-tert-butoxy-2-oxoethyl)-2,3-dihydro-1H-indol-3-yl]butanoate

A mixture of ethyl4-[1-(2-tert-butoxy-2-oxoethyl)-4-nitro-2,3-dihydro-1H-indol-3-yl]butanoatefrom Step C (1.10 g, 2.80 mmol) and 10% Pd/C (150 mg) in EtOH (50 mL)was stirred under an atmosphere of hydrogen (ca. 1 atm). After 18 b, thereaction was filtered through a Celite pad and concentrated in vacuo togive the title compound. MS: m/z/z 363 (M+1).

Step E. Lithium4-[4-amino-1-(2-tert-butoxy-2-oxoethyl)-2,3-dihydro-1H-indol-3-yl]butanoate

To a solution of ethyl4-[4-amino-1-(2-tert-butoxy-2-oxoethyl)-2,3-dihydro-1H-indol-3-yl]butanoatefrom Step D (1.00 g, 2.76 mmol) in THF (30 mL), EtOH (15 mL) and H₂O (15mL) was added 1.0 N lithium hydroxide (2.76 mL, 2.76 mmol). After 15min, 1 N aqueous HCl was added to adjust the solution to pH 7 and themixture was concentrated in vacuo to give the title compound, which wasof sufficient purity for use in the next step. MS: m/z=335 (M+1).

Step F. tert-Butyl(6-oxo-2a,3,4,5,6,7-hexahydroazocino[4,3,2-cd]indol-1(2H)-yl)acetate,Enantiomer A

A mixture of lithium4-[4-amino-1-(2-tert-butoxy-2-oxoethyl)-2,3-dihydro-1H-indol-3-yl]butanoatefrom Step E (900 mg, 2.69 mmol), EDC (1.29 g, 6.73 mmol), HOAT (916 mg,6.73 mmol), and N,N-diisopropylethylamine (0.94 mL, 5.38 mmol) wasstirred in DMF (10 mL) at ambient temperature for 4 h, then concentratedunder reduced pressure. The residue was partitioned between saturatedaqueous NaHCO₃ (5 mL) and EtOAc (50 mL). The organic layer was washedwith H₂O (5 mL), then 10% aqueous citric acid (5 mL), then dried overNa₂SO₄, filtered, and concentrated in vacuo. The crude product waspurified by silica gel chromatography, eluting with a gradient ofhexane:EtOAc—80:20 to 0:100, to give the racemic product. Theenantiomers were resolved by HPLC, utilizing a Chiralpak AS column andeluting with CH₃CN:MeOH—25:75. The first major peak to elute wastert-butyl(6-oxo-2a,3,4,5,6,7-hexahydroazocino[4,3,2-cd]indol-1(2H)-yl)acetate,enantiomer A, the title compound, and the second major peak to elute wastert-butyl(6-oxo-2a,3,4,5,6,7-hexahydroazocino[4,3,2-cd]indol-1(2B)-yl)acetate,enantiomer B. MS: m/z=317 (M+1).

Step G. tert-Butyl(7-methyl-6-oxo-2a,3,4,5,6,7-hexahydroazocino[4,3,2-cd]indol-1(2H)-yl)aceticAcid, Enantiomer A

To a solution of tert-butyl(6-oxo-2a,3,4,5,6,7-hexahydroazocino[4,3,2-cd]indol-1(2H)-yl)acetate,enantiomer A, from Step F (20 mg, 0.063 mmol) in DMF (0.5 mL) at ambienttemperature was added sodium hydride (3 mg of a 60% dispersion inmineral oil, 0.075 mmol). The reaction mixture was stirred for 5 min,then iodomethane (10 mg, 0.070 mmol) was added and stirring wascontinued for 10 min. The reaction was quenched with saturated aqueousNaHCO₃ (1 mL) and extracted with EtOAc (2×3 mL). The combined organicextracts were dried over Na₂SO₄, filtered, and concentrated in vacuo togive the title compound. MS: m/z=331 (M+1).

Step H.(7-Methyl-6-oxo-2a,3,4,5,6,7-hexahydroazocino[4,3,2-cd]indol-1(2H)-yl)aceticAcid, Enantiomer A

A solution of tert-butyl(7-methyl-6-oxo-2a,3,4,5,6,7-hexahydroazocino[4,3,2-cd]indol-1(2H)-yl)acetate,enantiomer A, from Step G (18 mg, 0.057 mmol) in EtOAc (1 mL) wassaturated with HCl (g), aged at ambient temperature for 10 min, thenresaturated with HCl (g). After a further 10 min, the mixture wasconcentrated in vacuo to give the title compound. MS: m/z=275 (M+1).

(5-Oxo-3,4,5,6-tetrahydro-1H-azepino[4,3,2-cd]indol-1-yl)acetic AcidStep A. Ethyl 4-(4-nitro-1H-indol-3-yl)propanoate

A mixture of 4-nitroindole (1.00 g, 6.17 mmol), Meldrum's acid (889 mg,6.17 mmol), proline (36 mg, 0.31 mmol), and formaldehyde (37% in H₂O,0.50 mL, 6.17 mmol) was stirred in CH₃CN (4 mL) at ambient temperaturefor 18 h. The reaction mixture was quenched with H₂O (20 mL) andextracted with EtOAc (2×20 mL). The combined organic extracts were driedover Na₂SO₄, filtered, and concentrated in vacuo. After drying underhigh vacuum, the solid residue was dissolved in pyridine (16 mL) andEtOH (4 mL). To the resulting solution was added copper powder (50 mg,0.79 mmol) and the mixture was heated at reflux for 2 h then allowed tocool. The solvent was removed in vacuo, and the residue was partitionedbetween saturated aqueous NaHCO₃ (25 mL) and EtOAc (50 mL). The organicextract was dried over Na₂SO₄, filtered, and concentrated in vacuo. Thecrude product was purified by silica gel chromatography, eluting with agradient of hexane:CH₂Cl₂—20:80 to 0:100, to give the title compound.MS: m/z=263 (M+1).

Step B. Ethyl3-[1-(2-tert-butoxy-2-oxoethyl)-4-nitro-1H-indol-3-yl]propanoate

To a solution of ethyl 4-(4-nitro-1H-indol-3-yl)propanoate from Step A(860 mg, 3.28 mmol) in DMF (15 mL), was added sodium hydride (142 mg ofa 60% dispersion in mineral oil, 3.55 mmol). After 5 min, tert-butylbromoacetate (0.581 mL, 3.94 mmol) was added dropwise and the reactionmixture was stirred at room temperature for 10 min then quenched withH₂O and extracted with CHCl₃ (3×35 mL). The combined organic extractswere dried over Na₂SO₄, filtered, and concentrated in vacuo. The crudeproduct was purified by silica gel chromatography, eluting with agradient of hexane:EtOAc—90:10 to 30:70, to give the title compound. MS:m/z=321 (M—C₄H₇).

Step C. Ethyl3-[4-amino-1-(2-tert-butoxy-2-oxoethyl)-1H-indol-3-yl]propanoate

A mixture of ethyl3-[1-(2-tert-butoxy-2-oxoethyl)-4-nitro-1H-indol-3-yl]propanoate fromStep B (1.20 g, 3.19 mmol) and 10% Pd/C (150 mg) in EtOH (100 mL) wasstirred under an atmosphere of hydrogen (ca. 1 atm). After 1 h, thereaction mixture was filtered through a Celite pad and concentrated invacuo to give the title compound. MS: m/z=347 (M+1).

Step D. tert-Butyl(5-oxo-3,4,5,6-tetrahydro-1H-azepino[4,3,2-cd]indol-1-yl)acetate

To a solution of ethyl3-[4-amino-1-(2-tert-butoxy-2-oxoethyl)-1H-indol-3-yl]propanoate fromStep C (1.00 g, 2.89 mmol) in toluene (50 mL) was addedp-toluenesulfonic acid monohydrate (5 mg, 0.026 mmol) and the mixturewas heated at reflux. After 2 h, the reaction was allowed to cool toambient temperature and the mixture was washed with saturated aqueousNaHCO₃ (10 mL). The organic layer was dried over Na₂SO₄, filtered, andconcentrated in vacuo. The crude product was purified by silica gelchromatography, eluting with a gradient of CH₂Cl₂:MeOH—100:0 to 92:8, togive the title compound. MS: m/z=301 (M+1).

Step E. (5-Oxo-3,4,5,6-tetrahydro-1H-azepino[4,3,2-cd]indol-1-yl)aceticAcid

To a solution of tert-butyl(5-oxo-3,4,5,6-tetrahydro-1H-azepino[4,3,2-cd]indol-1-yl)acetate fromStep D (100 mg, 0.33 mmol) in (1 mL) was added TFA (0.25 mL, 3.3 mmol)and the resulting mixture was stirred at ambient temperature for 1 h.The mixture was concentrated in vacuo to give the title compound. MS:m/z=245 (M+1).

(5-Oxo-2,2a,3,4,5,6-hexahydro-1H-azepino[4,3,2-cd]indol-1-yl)aceticAcid, Enantiomer A Step A. (±)-Ethyl3-(4-nitro-2,3-dihydro-1H-indol-3-yl)propanoate

Triethylsilane (16 mL, 99 mmol) was added to a solution of ethyl4-(4-nitro-1H-indol-3-yl)propanoate (1.30 g, 4.96 mmol, described inIntermediate 39) in TFA (25 mL). After 1 h, the reaction mixture wasconcentrated in vacuo and the residue was purified by silica gelchromatography, eluting with a gradient of CHCl₃:MeOH—100:0 to 94:6, togive the title compound. MS: m/z=265 (M+1).

Step B. (±)-Ethyl3-[1-(2-tert-butoxy-2-oxoethyl)-4-nitro-2,3-dihydro-1H-indol-3-yl]propanoate

To a solution of (±)-ethyl3-(4-nitro-2,3-dihydro-1H-indol-3-yl)propanoate from Step A (980 mg,3.71 mmol), sodium carbonate (590 mg, 5.56 mmol), and potassium iodide(123 mg, 0.74 mmol) in acetone (10 mL) was added tert-butyl bromoacetate(16.4 mL, 111 mmol). The mixture was heated at reflux for 18 h, thencooled to ambient temperature and concentrated in vacuo. The residue waspartitioned between H₂O (30 mL) and EtOAc (2×60 mL) and the organicextracts were dried over Na₂SO₄, filtered, and concentrated in vacuo.The crude product was purified by silica gel chromatography, elutingwith a gradient of hexane:EtOAc—100:0 to 65:35, to give the titlecompound. MS: m/z=379 (M+1).

(5-Oxo-2,2a,3,4,5,6-hexahydro-1H-azepino[4,3,2-cd]indol-1-yl)aceticAcid, Enantiomer A

Essentially following the procedures described for Intermediate 39, butusing (±)-ethyl3-[1-(2-tert-butoxy-2-oxoethyl)-4-nitro-2,3-dihydro-1H-indol-3-yl]propanoatein place of ethyl3-[1-(2-tert-butoxy-2-oxoethyl)-4-nitro-1H-indol-3-yl]propanoate, andresolving the racemate into pure enantiomers in analogy withIntermediate 47, the title compound was prepared. MS: m/z=303 (M+1).

Sodium(7-chloro-2,5-dioxo-5,6-dihydro-4H-imidazo[1,5,4-de]quinoxalin-1(2H)-yl)acetateStep A. 5-Chloro-2,1,3-benzoselenadiazole

A solution of 4-chlorobenzene-1,2-diamine (1.50 g, 10.5 mmol) in EtOH(15 mL) was heated to reflux and selenium dioxide (1.28 g, 11.5 mmol)was added. The reaction was refluxed for 30 min and cooled to ambienttemperature. The precipitated solid was filtered, washed thoroughly withH₂O and dried under high vacuum to give the title compound. MS: m/z=219(M+1).

Step B. 5-Chloro-4-nitro-2,1,3-benzoselenadiazole

A solution of 5-chloro-2,1,3-benzoselenadiazole from Step A (800 mg,1.80 mmol) in conc. H₂SO₄ (12 mL) was cooled to 0° C. and 90% HNO₃ (0.8mL) was added. After 30 min the reaction was cooled to 0° C. and dilutedwith H₂O (10 mL). The solid was filtered off and washed with cold H₂O toyield the title compound. MS: m/z=263 (M+1).

Step C. 5-Chloro-4-nitro-1,3-dihydro-2H-benzimidazol-2-one

A solution of 5-chloro-4-nitro-2,1,3-benzoselenadiazole from Step B (650mg, 2.47 mmol) in conc. HCl (4 mL) and 48% aqueous HI (2 mL) was stirredat ambient temperature for 2 h. The reaction was diluted with a 1:1saturated aqueous solution of NaHSO₄ and Na₂CO₃ (20 mL) and thenadjusted to pH 10 using 10 M aqueous NaOH. The mixture was extractedwith EtOAc (3×110 mL) and the organic extracts dried over Na₂SO₄,filtered, and concentrated in vacuo. The resulting dark red solid wasdissolved in CH₃CN (4 mL) and phosgene was added (20% solution intoluene, 1.5 mL, 3.2 mmol). The reaction mixture was stirred for 1 h,then diluted with toluene. Filtration of the resultant solid gave thetitle compound. MS: m/z=214 (M+1).

Step D. Dimethyl2,2′-(5-chloro-4-nitro-2-oxo-1H-benzimidazole-1,3-diyl)diacetate

Cesium carbonate (1.16 g, 3.60 mmol) was added to a solution of5-chloro-4-nitro-1,3-dihydro-2H-benzimidazol-2-one from Step A (255 mg,1.20 mmol) and methyl bromoacetate (0.23 mL, 2.40 mmol) in DMF (5 mL).After 1.5 h, the reaction was quenched with H₂O (30 mL) and the solidprecipitate was collected by filtration to give the title compound. MS:m/z=359 (M+1).

Step E. Methyl(7-chloro-2,5-dioxo-5,6-dihydro-4H-imidazo[1,5,4-de]quinoxalin-1(2H)-yl)acetate

To a solution of dimethyl2,2′-(5-chloro-4-nitro-2-oxo-1H-benzimidazole-1,3-diyl)diacetate (100mg, 0.28 mmol) from Step D in AcOH (1.0 mL) and water (0.11 mL) wasadded fine granular iron (78 mg, 1.4 mmol) and the slurry was heated at70° C. for 1 h. The reaction was cooled, filtered, concentrated anddissolved in DMF (4 mL). The DMF solution was added dropwise to H₂O (30mL) with stirring and the precipitate was isolated by filtration to givethe title compound. MS: m/z 296 (M+1).

Step F. Sodium(7-chloro-2,5-dioxo-5,6-dihydro-4H-imidazo[1,5,4-de]quinoxalin-1(2H)-yl)acetate

Essentially following the procedures described for Intermediate 45, butusing methyl(7-chloro-2,5-dioxo-5,6-dihydro-4H-imidazo[1,5,4-de]quinoxalin-1(2R)-yl)acetatein place of methyl(6-methyl-2,5-dioxo-5,6-dihydro-4H-imidazo[1,5,4-de]quinoxalin-1(2H)-yl)acetate,the title compound was prepared MS: m/z=282 (M+1).

Sodium(2,4-dioxo-4,5-dihydro-3H-1,2a,5,7-tetraazaacenaphthylen-1(2H)-yl)acetateStep A. 2,6-Dichloro-3-nitro-pyridin-4-amine

To a solution of 2,6-dichloro-4-aminopyridine (5.0 g, 30.6 mmol) inconc. H₂SO₄ (25 mL) at 0° C. in an ice-acetone bath was added 90% HNO₃(10 mL) dropwise. The reaction mixture was warmed to ambient temperatureand stirred for 1 h then poured onto ice (100 g). The solid precipitatewas isolated by filtration, washed with cold H₂O and dried under highvacuum. The resulting solid was dissolved in conc. H₂SO₄ (50 mL) andheated at 100° C. for 20 min. The reaction mixture was poured onto ice(150 g) and neutralized with conc. NH₄OH while maintaining thetemperature below 20° C. The precipitate was isolated by filtration,washed with cold H₂O, and dried to yield the title compound. MS: m/z=209(M+1).

Step B. 2,6-Dichloro-pyridine-3,4-diamine

To a solution of 2,6-dichloro-3-nitro-pyridin-4-amine (2.6 g, 14.4 mmol)from Step A in MeOH (150 mL) was added Raney Nickel catalyst (2 g) andthe reaction agitated under a hydrogen atmosphere in a Parr apparatus(35 p.s.i.) for 2 h. The reaction mixture was filtered through a pad ofCelite and concentrated to yield the title compound. MS: w/z=179 (M+1).

Step C. 4,6-Dichloro-1,3-dihydro-2H-imidazo[4,5-c]pyridin-2-one

A mixture of 2,6-dichloro-3,4-dihydropyridine-3,4-diamine (500 mg, 2.8mmol) from Step B and urea (1.0 g, 16.8 mmol) was stirred as a melt at165° C. for 4 h, then cooled and H₂O (100 mL) was added. The aqueousmixture was heated at reflux until all solid dissolved and the solutionwas allowed to cool and aged for 18 h. The precipitate was isolated byfiltration to give the title compound. MS: m/z=205 (M+1).

Step D. 4,6-Dichloro-7-nitro-1,3-dihydro-2H-imidazo[4,5-c]pyridin-2-one

To a solution of 4,6-dichloro-1,3-dihydro-2H-imidazo[4,5-c]pyridin-2-one(0.6 g, 2.94 mmol) from Step C in conc. H₂SO₄ (15 mL) was added KNO₃(2.97 g, 29.4 mmol) and the reaction mixture was heated at 125° C. for 2h. After cooling, the reaction was mixed with ice and the solidprecipitate was isolated by filtration and washed with cold 1420 to givethe title compound. MS: m/z=250 (M+1).

Step E. Dimethyl22′-(4,6-dichloro-7-nitro-2-oxo-1H-imidazo[4,5-c]pyridine-1,3-diyl)diacetate

Cesium carbonate (2.39 g, 7.33 mmol) was added to a solution of4,6-dichloro-7-nitro-1,3-dihydro-2H-imidazo[4,5-c]pyridin-2-one fromStep D (610 mg, 2.45 mmol) and methyl bromoacetate (0.47 mL, 5.02 mmol)in DMF (5 mL). After 1.5 h, the reaction was quenched with H₂O (30 mL)and the solid precipitate was collected by filtration to give the titlecompound. MS: m/z=394 (M+1).

Step F. Methyl(2,4-dioxo-4,5-dihydro-3H-1,2a,5,7-tetraazaacenaphthylen-1(2T)-yl)acetate

A mixture of dimethyl2,2′-(4,6-dichloro-7-nitro-2-oxo-1H-imidazo[4,5-c]pyridine-1,3-diyl)diacetate(40 mg, 0.10 mmol) from Step E and 10% Pd/C (12 mg) in MeOH (2 mL) wasstirred under an atmosphere of hydrogen (ca. 1 atm) for 6 h. Thereaction mixture was filtered through a pad of Celite and concentratedin vacuo. The crude material was heated at 80° C. for 2 h in toluene (2mL) and AcOH (2 mL) then concentrated to give the title compound. MS:m/z=263 (M+1).

Step G. Sodium(2,4-dioxo-4,5-dihydro-3H-1,2a,5,7-tetraazaacenaphthylen-1(2H)-yl)acetate

Essentially following the same procedures described for Intermediate 31,but using methyl(2,4-dioxo-4,5-dihydro-3H-1,2a,5,7-tetraazaacenaphthylen-1(2H)-yl)acetatein place of methyl(2,5-dioxo-5,6-dihydro-4H-imidazo[1,5,4-de]quinoxalin-1(2H)-yl)acetate,the title compound was prepared. MS: m/z=249 (M+1).

Sodium(2,4-dioxo-4,5-dihydro-3H-1,2a,5,6-tetraazaacenaphthylen-1(2H)-yl)acetateStep A. 1,3-Dihydro-2H-imidazo[4,5-c]pyridin-2-one

A combination of pyridine-3,4-diamine (1.0 g, 9.16 mmol) and urea (3.3g, 54.9 mmol) were stirred as a melt at 165° C. for 4 h, then cooled andH₂O (100 mL) was added. The aqueous mixture was heated at reflux untilall solid dissolved and the solution was allowed to cool and aged for 18h. The precipitate was isolated by filtration to give the titlecompound. MS: m/z=136 (M+1).

Step B. Sodium(2,4-dioxo-4,5-dihydro-3H-1,2a,5,6-tetraazaacenaphthylen-1(2H)-yl)acetate

Essentially following the procedures described for Intermediate 42, butusing 1,3-dihydro-2H-imidazo[4,5-c]pyridin-2-one in place of4,6-dichloro-1,3-dihydro-2H-imidazo[4,5-c]pyridin-2-one, the titlecompound was prepared. MS: m/z=249 (M+1).

Sodium (2-oxo-2,3-dihydro-1H-pyrrolo[2,3-de]quinoxalin-6-yl)acetate StepA. N,N-Dimethyl-1-(7-nitro-1H-indol-3-yl)methanamine

A mixture of 7-nitro-1H-indole (3 g, 18.5 mmol), 40% aqueousdimethylamine (3.12 mL, 27.7 mmol) and 37% aqueous formaldehyde (1.57mL, 19.3 mmol) was stirred for three days at ambient temperature. Thereaction mixture was diluted with H₂O (20 mL) followed 15% aqueous NaOH(200 mL) and extracted with CHCl₃ (3×200 mL). The combined organicextracts were dried over Na₂SO₄, filtered, and concentrated in vacuo togive the title compound in sufficient purity for use in the next step.MS: m/z=181 (M+1).

Step B. Methyl (7-nitro-1H-indol-3-yl)acetate

A solution of N,N-dimethyl-1-(7-nitro-1H-indol-3-yl)methanamine fromStep A (3.3 g, 18.5 mmol) in DMF (3 mL), H₂O (3 mL), THF (150 mL) andiodomethane (2.85 mL, 45.7 mmol) was heated at reflux for 15 min as awhite precipitate formed. Potassium cyanide (6.0 g, 92.1 mmol) was addedand reflux was continued for 2 h. The cooled solution was filtered andconcentrated under reduced pressure and the residue was triturated withMeOH to give (7-nitro-1H-indol-3-yl)acetonitrile as a yellow solid. Asuspension of this solid in MeOH (10 mL) was cooled to 0° C. and HCl (g)was bubbled in slowly for 30 min. The reaction mixture was aged for 1 h,then concentrated in vacuo. To the residue was added 6 M aqueous HCl (20mL) and the mixture was extracted with EtOAc (3×20 mL). The combinedorganic extracts were washed with saturated aqueous NaHCO₃ (50 mL), thenbrine (20 mL), dried over Na₂SO₄, filtered, and concentrated to give thetitle compound. MS: m/z=235 (M+1).

Step C. Dimethyl 2,2′-(7-nitro-1H-indole-1,3-diyl)diacetate

To a solution of methyl (7-nitro-1H-indol-3-yl)acetate from Step B (545mg, 2.71 mmol) was added cesium carbonate (927 mg, 2.85 mmol) and methylbromoacetate (0.26 mL, 2.84 mmol) in DMF (10 mL). The reaction mixturewas stirred at ambient temperature for 18 h, then quenched with H₂O (50mL). The solid precipitate was collected by filtration to give the titlecompound. MS: m/z=274 (M+1).

Step D. Sodium(2-oxo-2,3-dihydro-1H-pyrrolo[1,2,3-de]quinoxalin-6-yl)acetate

Essentially following the procedures described for Intermediate 31, butusing dimethyl 2,2′-(7-nitro-1H-indole-1,3-diyl)diacetate in place ofdimethyl 2,2′-(4-nitro-2-oxo-1H-benzimidazole-1,3-diyl)diacetate, thetitle compound was prepared. MS: m/z=231 (M+1).

Sodium(6-methyl-2,5-dioxo-5,6-dihydro-4H-imidazo[1,5,4-de]quinoxalin-1(2H)-yl)acetateStep A. Methyl(6-methyl-2,5-dioxo-5,6-dihydro-4H-imidazo[1,5,4-de]quinoxalin-1(2H)-yl)acetate

To a solution of methyl(2,5-dioxo-5,6-dihydro-4H-imidazo[1,5,4-de]quinoxalin-1(2B)-yl)acetate(300 mg, 1.15 mmol, described in Intermediate 31) in DMF (5 mL) wereadded cesium carbonate (748 mg, 2.3 mmol) and iodomethane (326 mg, 2.3mmol). After 16 h, the reaction mixture was quenched with brine (20 mL)and extracted with EtOAc (50 mL). The organic layer was dried overNa₂SO₄, filtered, and concentrated in vacuo to give the title compound.MS: m/z=276 (M+1).

Step B. Sodium(6-methyl-2,5-dioxo-5,6-dihydro-4H-imidazo[1,5,4-de]quinoxalin-1(2H)-yl)acetate

To a solution of methyl(6-methyl-2,5-dioxo-5,6-dihydro-4H-imidazo[1,5,4-de]quinoxalin-1(2H)-yl)acetatefrom Step A (225 mg, 0.817 mol) in MeOH (10 mL) was added 1.0 N sodiumhydroxide (1.2 mL, 1.2 mmol). After 3 h, the reaction mixture wasneutralized with 1 N aqueous HCl and concentrated to give the titlecompound. MS: m/z=262 (M+1).

Lithium (4-oxo-4,5-dihydropyrrolo[4,3,2-de]quinolin-1(3H)-yl)acetateStep A. N,N-Dimethyl-1-(4-nitro-1H-indol-3-yl)methanamine

N,N,N′,N′-Tetramethyldiaminomethane (2.2 mL, 15.6 mol) in acetic acid(30 mL) was added dropwise over 60 min to a solution of 4-nitroindole(2.30 g, 14.2 mol) in acetic acid (30 mL). After 3.5 h, the reaction wascooled to 0° C., and 20% aqueous sodium hydroxide was added to adjustthe pH to 11. The mixture was extracted with CHCl₃ (3×300 mL) and thecombined organic extracts were dried over Na₂SO₄, filtered, andconcentrated in vacuo to give the title compound. MS: m/z=220 (M+1).

Step B. (4-Nitro-1H-indol-3-yl)acetonitrile

Potassium cyanide (9.20 g, 141 mmol) in H₂O (80 mL) was added to asolution of N,N-dimethyl-1-(4-nitro-1H-indol-3-yl)methanamine from StepA (3.10 g, 14.1 mmol) in DMF (80 mL) and the mixture was heated atreflux for 1 h, then cooled to ambient temperature and partitionedbetween H₂O (200 mL) and EtOAc (400 mL). The organic layer was driedover Na₂SO₄, filtered, and concentrated in vacuo. The crude product waspurified by silica gel chromatography, eluting with a gradient ofhexane:EtOAc—100:0 to 0:100, to give the title compound. MS: m/z=265(M+Na+CH₃CN).

Step C. tert-Butyl [3-(cyanomethyl)-4-nitro-1H-indol-1-yl]acetate

Sodium hydride (198 mg of a 60% dispersion in mineral oil, 5.0 mmol) wasadded to a solution of (4-nitro-1H-indol-3-yl)acetonitrile from Step B(910 mg, 4.52 mmol) in DMF (15 mL). After 10 min, tert-butylbromoacetate (0.801 mL, 5.4 mmol) was added dropwise and the reactionmixture was stirred at ambient temperature for 1.5 h. The mixture waspartitioned between H₂O (50 mL) and EtOAc (100 mL) and the organicextract was washed with brine, dried over Na₂SO₄, filtered, andconcentrated in vacuo. The crude product was purified by silica gelchromatography, eluting with a gradient of hexane:EtOAc—100:0 to 0:100,to give the title compound. MS: m/z=316 (M+1).

Step D. 2,2′-(4-Nitro-1H-indole-1,3-diyl)diacetic Acid

To a solution of tert-butyl[3-(cyanomethyl)-4-nitro-1H-indol-1-yl]acetate from Step C (920 mg, 2.92mol) in ethanol (50 mL) was added 1.0 N aqueous sodium hydroxide (14.6mL, 14.6 mmol) and the mixture was heated at reflux for 18 h. Anadditional amount of 1.0 N sodium hydroxide (15 mL, 15 mmol) was addedto the reaction, most of the EtOH was distilled out of the flask, andthe mixture was heated at reflux for a further 21 h. The reactionmixture was cooled to 0° C. and concentrated HCl was added to adjust thepH to 1-2. The mixture was extracted with EtOAc (2×150 mL) and thecombined organic extracts were dried over Na₂SO₄, filtered, andconcentrated in vacuo to give the title compound. MS: m/z=279 (M+1).

Step E. Diethyl 2,2′-(4-nitro-1H-indole-1,3-diyl)diacetate

Concentrated sulfuric acid (0.02 mL) was added to a solution of2,2′-(4-nitro-1H-indole-1,3-diyl)diacetic acid from Step D (742 mg, 2.67mol) in EtOH (100 mL) and the mixture was heated at reflux for 9 h. Thereaction mixture was allowed to cool to ambient temperature and wasconcentrated to a volume of 30 mL in vacuo. The solution was partitionedbetween EtOAc (300 mL) and aqueous NaHCO₃ (100 mL) and the organic layerwas dried over Na₂SO₄, filtered, and concentrated in vacuo to give thetitle compound. MS: m/z=335 (M+1).

Step F. Diethyl 2,2′-(4-amino-1H-indole-1,3-diyl)diacetate

A mixture of diethyl 2,2′-(4-nitro-1H-indole-1,3-diyl)diacetate fromStep E (140 mg, 0.419 mmol) and 10% Pd/C (20 mg) in EtOH (20 mL) wasstirred under an atmosphere of hydrogen (ca-1 atm). After 1.5 h, thereaction mixture was filtered through a Celite pad and concentrated invacuo to give the title compound. MS: m/z=305 (M+1).

Step G. Ethyl(4-oxo-4,5-dihydropyrrolo[4,3,2-de]quinolin-1(3H)-yl)acetate

To a solution of diethyl 2,2′-(4-amino-1H-indole-1,3-diyl)diacetate fromStep F (83 mg, 0.273 mmol) in toluene (8 mL) was added p-toluenesulfonicacid monohydrate (5 mg, 0-026 mmol) and the mixture was heated atreflux. After 2 h, the reaction was allowed to cool to ambienttemperature and the mixture was partitioned between EtOAc (40 mL) andaqueous NaHCO₃ (15 mL). The organic layer was washed with brine, driedover Na₂SO₄, filtered, and concentrated in vacuo. The crude product waspurified by silica gel chromatography, eluting with a gradient ofCH₂Cl₂:MeOH—100:0 to 92:8, to give the title compound. MS: m/z=259(M+1).

Step H. Lithium(4-oxo-4,5-dihydropyrrolo[4,3,2-de]quinolin-1(3H)-yl)acetate

To a solution of ethyl(4-oxo-4,5-dihydropyrrolo[4,3,2-de]quinolin-1(3B)-yl)acetate from Step G(79 mg, 0.306 mmol) in ethanol (3 mL) and water (0.5 mL) was addeddropwise 1.0 N aqueous lithium hydroxide (0.34 mL, 0.34 mmol). After 5min, 1 N aqueous HCl was added to adjust the mixture to pH 7 and thesolution was concentrated in vacuo to give the title compound. MS:m/z=231 (M+1).

Lithium(4-oxo-2a,3,4,5-tetrahydropyrrolo[4,3,2-de]quinolin-1(2H-yl)acetate,Enantiomer B Step A. Methyl (4-nitro-1H-indol-3-yl)(oxo)acetate

Diphosphoryl chloride (0.938 mL, 6.80 mmol) was added dropwise to asolution of 4-nitroindole (1.00 g, 6.17 mmol) and methylpyrrolidinylglyoxylate (Downie et al., Tetrahedron, 1993, 49, 4015-4034) (1.10 g,6.80 mmol) at 0° C. and the mixture was allowed to warm to ambienttemperature over 3 h. MeOH, then saturated aqueous NaHCO₃ were added tothe reaction at 0° C. and the solution was extracted with CH₂Cl₂ (3×50mL). The combined organic extracts were dried over Na₂SO₄, filtered, andconcentrated in vacuo until crystals formed. The crystals were collectedby vacuum filtration and two more crops were isolated from the filtrateto give the title compound. MS: m/z=249 (M+1).

Step B. (±)-Methyl (4-nitro-2,3-dihydro-1H-indol-3-yl)acetate

Triethylsilane (13 mL, 80.6 mmol) was added to a solution of methyl(4-nitro-1H-indol-3-yl)(oxo)acetate from Step A (1.00 g, 4.03 mmol) inTFA (15 mL). After 3 h, the reaction mixture was concentrated in vacuoand the residue was purified by silica gel chromatography, eluting witha gradient of CHCl₃:MeOH—100:0 to 98:2, to give the title compound. MS:m/z=237 (M+1).

Step C. (±)-Ethyl methyl2,2′-(4-nitro-2,3-dihydro-1H-indole-1,3-diyl)diacetate

To a solution of (±)-methyl (4-nitro-2,3-dihydro-1H-indol-3-yl)acetatefrom Step B (700 mg, 2.97 mmol), sodium carbonate (471 mg, 4.44 mmol),and potassium iodide (98 mg, 0.59 mmol) in acetone (15 mL) was addedethyl bromoacetate (9.9 mL, 88.9 mmol). The mixture was heated at refluxfor 18 h, then cooled to ambient temperature and concentrated in vacuo.The residue was partitioned between H₂O (15 mL) and EtOAc (2×40 mL) andthe organic extracts were washed with brine, dried over Na₂SO₄,filtered, and concentrated in vacuo to a volume of 50 mL. Hexane wasadded to the EtOAc solution and a precipitate formed. The desiredcrystals were collected by vacuum filtration to give the title compound.MS: m/z=323 (M+1).

Step D. (±)-Ethyl methyl2,2′-(4-amino-2,3-dihydro-1H-indole-1,3-diyl)diacetate

A mixture of (±)-ethyl methyl2,2′-(4-nitro-2,3-dihydro-1H-indole-1,3-diyl)diacetate from Step C (550mg, 1.71 mmol) and 10% Pd/C (40 mg) in EtOH (10 mL) was stirred under anatmosphere of hydrogen (ca. 1 atm). After 3 h, the reaction was filteredthrough a Celite pad and concentrated in vacuo to give the titlecompound. MS: m/z=293 (M+1).

Step E. Ethyl(4-oxo-2a,3,4,5-tetrahydropyrrolo[4,3,2-de]quinolin-1(2H)-yl)acetate,Enantiomer B

To a solution of (*)-ethyl methyl2,2′-(4-amino-2,3-dihydro-1H-indole-1,3-diyl)diacetate from Step D (490mg, 1.70 mmol) in toluene (35 mL) was added p-toluenesulfonic acidmonohydrate (5 mg, 0.026 mmol) and the mixture was heated at reflux for48 h. The mixture was cooled to ambient temperature and was partitionedbetween saturated aqueous NaHCO₃ (5 mL) and EtOAc (40 mL). The organiclayer was dried over Na₂SO₄, filtered, and concentrated in vacuo. Thecrude product was purified by silica gel chromatography, eluting with agradient of CHCl₃:EtOAc—90:10 to 40:60, to give the racemic product. Theenantiomers were resolved by HPLC, utilizing a Chiralpak AS column andeluting with MeOH. The first major peak to elute was ethyl(4-oxo-2a,3,4,5-tetrahydropyrrolo[4,3,2-de]quinolin-1(2H)-yl)acetate,enantiomer A, and the second major peak to elute was ethyl(4-oxo-2a,3,4,5-tetrahydropyrrolo[4,3,2-de]quinolin-1(2H)-yl)acetate,enantiomer B, the title compound. MS: m/z=261 (M+1).

Step F. Lithium(4-oxo-2a,3,4,5-tetrahydropyrrolo[4,3,2-de]quinolin-1(2H)-yl)acetate,Enantiomer B

To a solution of ethyl(4-oxo-2a,3,4,5-tetrahydropyrrolo[4,3,2-de]quinolin-1(2B)-yl)acetate,enantiomer B, from Step E (55 mg, 0.211 mmol) in THF (1 mL), EtOH (1 mL)and H₂O (1 mL) was added 1.0 N lithium hydroxide (0.232 mL, 0.232 mmol).After 15 min, 1 N aqueous HCl was added to adjust the solution to pH 7and the mixture was concentrated in vacuo to give the title compound.MS: m/z=233 (M+1).

2a-(2,2-Difluoroethyl)-1,2,2a,5-tetrahydropyrrolo[4,3,2-de]quinolin-4(3)-one,Enantiomer A Step A.2a-(2,2-Difluoroethyl)-1.22a,5-tetrahydropyrrolo[4,3,2-de]quinolin-4(3H)-one,enantiomer A

To a stirred solution of tert-butyl4-oxo-2a-(2-oxoethyl)-2a,3,4,5-tetrahydropyrrolo[4,3,2-de]quinolin-1(2B)-carboxylate,enantiomer A, (150 mg, 0.474 mmol, described in Intermediate 29) inCH₂Cl₂ (2 mL) at 0° C. was added DAST (0.125 mL, 0.948 mmol) and themixture was stirred for 1 h. Additional DAST (0.066 mL) was added andthe mixture was stirred for 1 h. To the resulting mixture was added TFA(2 mL) and stirring was continued for 1 h. The mixture was concentratedin vacuo and partitioned between saturated aqueous NaHCO₃ (10 mL) andCH₂Cl₂ (10 mL). The layers were separated and the aqueous layer furtherextracted with CH₂Cl₂ (2×10 mL). The combined organic layers were driedover Na₂SO₄, filtered, and concentrated in vacuo. The crude product waspurified by silica gel chromatography, eluting with a gradient ofCH₂Cl₂:MeOH—100:0 to 95:5, to give the title compound. MS: m/z=239(M+1).

(7R)-2-Acetyl-3′-methyl-6,8-dihydro-2′H,5H-spiro[cyclopenta[g]quinoline-7,4′-imidazolidine]-2′,5′-dioneStep A.(7R)-2-(1-Hydroethyl)-3′-methyl-6,8-dihydro-2H,5H-spiro[cyclopenta[g]quinoline-7,4-imidazolidine]-2′,5′-dione

To a suspension of(7R)-3′-methyl-2′,5′-dioxo-6,8-dihydrospiro[cyclopenta[g]quinoline-7,4′-imidazolidine]-2-carbaldehyde(90 mg, 0.305 mmol, described in Intermediate 13) in THF (20 mL) at −78°C. was added methyl magnesium bromide (0.31 mL of a 3 M solution inEt₂O, 0.93 mmol). The reaction mixture was stirred for 30 min at −78° C.and 2 h at ambient temperature. The reaction mixture was quenched by theaddition of water and partitioned between water (20 mL) and EtOAc (20mL). The layers were separated and the aqueous layer was furtherextracted with EtOAc (2×20 mL). The combined organic layers were driedover Na₂SO₄, filtered, and concentrated in vacuo to yield the titlecompound, which was used without further purification. MS: m/z=312(M+1).

Step B.(7R)-2-Acetyl-3′-methyl-6,8-dihydro-2H,5H-spiro[cyclopenta[g]quinoline-74′-imidazolidine]-2′,5′-dione

A mixture of(7R)-2-(1-hydroxyethyl)-3′-methyl-6,8-dihydro-2′H,5′H-spiro[cyclopenta[g]quinoline-7,4′-imidazolidine]-2′,5′-dionefrom Step A (95 mg, 0.305 mmol) and manganese dioxide (255 mg, 9.06mmol) in dioxane (5 mL) and CHCl₃ (5 mL) was heated at reflux for 48b.The reaction mixture was filtered through a pad of Celite, washing withCH₂Cl₂-MeOH, and the filtrate was concentrated under reduced pressure.The crude product was purified by silica gel chromatography, elutingwith a gradient of CH₂Cl₂:MeOH—100:0 to 95:5, to give the titlecompound. MS: m/z=310 (M+1).

tert-Butyl[(4-oxo-1,2,4,5-tetrahydropyrrolo[4,3,2-de]quinolin-2a(3H)-yl)methyl]carbamate,Enantiomer A Step A.(±)-2a-[(1,3-Dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]-2a,5-dihydropyrrolo[4,3,2-de]quinoline-2,4(1H,3H)-dione

To a stirred solution of(±)-2a,5-dihydropyrrolo[4,3,2-de]quinoline-2,4(1H,31)-dione (2.00 g,10.6 mmol, described in Intermediate 17) in degassed DMF (30 mL) at 0°C. was added sodium hydride (468 mg of a 60% dispersion in mineral oil,11.7 mmol). The mixture was stirred for 10 min, thenN-(bromomethyl)phthalimide (2.55 g, 10.6 mmol) was added and stirringwas continued for 2 h. An additional portion ofN-(bromomethyl)phthalimide (500 mg) was added and stirring was continuedfor 1 h. The reaction mixture was quenched with saturated aqueous NaHCO₃(100 mL) and extracted with EtOAc (3×50 mL). The combined organicextracts were dried over Na₂SO₄, filtered, and concentrated in vacuo.The crude product was purified by silica gel chromatography, elutingwith a gradient of CH₂Cl₂:MeOH—100:0 to 90:10, to give the titlecompound. MS: m/z=348 (M+1).

Step B.(±)-2a-(Aminomethyl)-2a,5-dihydropyrrolo[4,3,2-de]quinoline-2,4(1H,3R)-dione

A solution of(A)-2a-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]-2a,5-dihydropyrrolo[4,3,2-de]quinoline-2,4(1H,3H)-dionefrom Step A (2.30 g, 6.62 mmol) and hydrazine (1.05 mL, 33.1 mmol) inEtOH (30 mL) was heated at 70° C. for 2 h, then cooled to ambienttemperature and filtered. The filtrate was concentrated in vacuo. Thecrude product was purified by silica gel chromatography, eluting with agradient of CH₂Cl₂:MeOH:NH₄OH—100:0:0 to 90:9:1, to give the titlecompound. MS: m/z=218 (M+1).

Step C. (+A-tert-Butyl(2,4-dioxo-1,2,4,5-tetrahydropyrrolo[4,3,2-de]quinolin-2a(3H)-yl)methylcarbamate

To a solution of(±)-2a-(aminomethyl)-2a,5-dihydropyrrolo[4,3,2-de]quinoline-2,4(1H,33B)-dionefrom Step B (1.08 g, 4.97 mmol) and di-tert-butyl dicarbonate (1.30 g,5.97 mmol) in CH₂Cl₂ (20 mL) and EtOH (10 mL) was added triethylamine(1.39 mL, 9.94 mmol). The reaction mixture was stirred for 16 h and thenconcentrated in vacuo. The crude product was purified by silica gelchromatography, eluting with a gradient of CH₂Cl₂:MeOH:NH₄OH—100:0:0 to95:5:1, to give the title compound. MS: m/z=318 (M+1).

Step D. tert-Butyl[(4-oxo-1,2,4,5-tetrahydropyrrolo[4,3,2-de]quinolin-2a(3H)-yl)methyl]carbamateenantiomer A

To a solution of (±)-tert-butyl(2,4-dioxo-1,2,4,5-tetrahydropyrrolo[4,3,2-de]quinolin-2a(3H)-yl)methylcarbamatefrom Step C (1.20 g, 3.78 mmol) in THF (20 mL) at 0° C. was addedDIBAL-H (18.9 mL of a 1 M solution in toluene, 18.9 mmol). The reactionmixture was stirred for 2 h and then quenched by the slow addition ofsaturated aqueous sodium potassium tartrate (100 mL) and extracted withEtOAc (3×50 mL). The combined organic extracts were dried over Na₂SO₄,filtered, and concentrated in vacuo. The crude product was purified bysilica gel chromatography, eluting with a gradient ofCH₂Cl₂:MeOH:NH₄OH—100:0:0 to 95:5:1, to give (±)-tert-butyl[(2-oxo-1,2,4,5-tetrahydropyrrolo[4,3,2-de]quinolin-2a(3H)-yl)methyl]carbamate,which eluted first, and the racemic title compound, which eluted second.The enantiomers were resolved by HPLC, utilizing a ChiralPak AD columnand eluting with hexane:EtOH:Et₂NH—60:40:0.1. The first major peak toelute was tert-butyl[(4-oxo-1,2,4,5-tetrahydropyrrolo[4,3,2-de]quinolin-2a(3H)-yl)methyl]carbamate,enantiomer A, the title compound, and the second major peak to elute wastert-butyl[(4-oxo-1,2,4,5-tetrahydropyrrolo[4,3,2-de]quinolin-2a(3H)-yl)methyl]carbamate,enantiomer B. MS: m/z=304 (M+1).

(±)-tert-Butyl[(2-oxo-1,2,4,5-tetrahydropyrrolo[4,3,2-de]quinolin-2a(3)-yl)methyl]carbamateStep A. (±)-tert-Butyl[(2-oxo-1,2,4,5-tetrahydropyrrolo[4,3,2-de]quinolin-2a(3H)-yl)methyl]carbamate

The title compound was obtained from the same reaction as Intermediate50. The crude product was purified by silica gel chromatography, elutingwith a gradient of CH₂Cl₂:MeOH:NOH—100:0:0 to 95:5:1, to give the titlecompound, which eluted first, and (±)-tert-butyl[(4-oxo-1,2,4,5-tetrahydropyrrolo[4,3,2-de]quinolin-2a(3B)-yl)methyl]carbamate,which eluted second. MS: m/z=304 (M+1).

(7R)-3,3′-Dimethyl-2′,5′-dioxo-6,8-dihydrospiro[cyclopenta[g]quinoline-7,4′-imidazolidine]-2-carbaldehydeStep A.(7R)-3,3′-Dimethyl-2′,5′-dioxo-6,8-dihydrospiro[cyclopenta[g]quinoline-7,4′-imidazolidine]-2-carbaldehyde

Essentially following the procedures described for Intermediate 13, butusing trans-2-methyl-2-butenal in place of crotonaldehyde, the titlecompound was prepared. MS: m/z=327 (M+1+H₂O).

7-Fluoro-2a-methyl-1,22a,5-tetrahydropyrrolo[4,3,2-de]quinolin-4(3L)-one,Enantiomer A Step A. Dimethyl 2-(4-fluoro-2,6-dinitrophenyl)malonate

To a solution of dimethyl malonate (16.3 mL, 143 mmol) in DMA (100 mL)at ambient temperature was added potassium tert-butoxide (15.3 g, 136mmol). The reaction mixture was heated to 70° C. for 30 min, thenremoved from the oil bath. A solution of2-chloro-5-fluoro-1,3-dinitrobenzene (14.3 g, 64.9 mmol) in dioxane (70mL) was added drop wise over 30 min. The reaction mixture was stirredfor 10 min, then cooled and poured onto saturated aqueous NH₄Cl (500mL). The aqueous layer was extracted with EtOAc (250 mL) and Et₂O (2×250mL). The combined organic extracts were washed with H₂O (100 mL), driedover Na₂SO₄, and concentrated in vacuo to give the title compound, whichwas used without further purification. MS: m/z=317 (M+1).

Step B. Methyl (4-fluoro-2,6-dinitrophenyl)acetate

A solution of dimethyl 2-(4-fluoro-2,6-dinitrophenyl)malonate from StepA (20.5 g, 64.9 mmol) and lithium chloride (5.50 g, 130 mmol) in DMSO(120 mL) and water (2.34 mL) was heated at 90° C. for 3 h, then cooledand poured onto H₂O (400 mL). The aqueous layer was extracted with Et₂O(3×250 mL). The combined organic layers were washed with brine (100 mL),dried over Na₂SO₄, and concentrated in vacuo. The crude product waspurified by silica gel chromatography, eluting with a gradient ofhexanes:EtOAc—100:0 to 80:20, to give the title compound. MS: m/z=259(M+1).

Step C. (±)-4-Ethyl 1-methyl 2-(4-fluoro-2,6-dinitrophenyl)succinate

To a solution of methyl (4-fluoro-2,6-dinitrophenyl)acetate from Step B(9.51 g, 36.8 mmol) and ethyl bromoacetate (8.17 mL, 73.6 mmol) in DMF(100 mL) was added cesium carbonate (18.0 g, 55.2 mmol). The reactionmixture was stirred for 16 h and then poured onto H₂O (500 mL). Theaqueous layer was extracted with EtOAc (3×250 mL). The combined organiclayers were washed with H₂O (100 mL), dried over Na₂SO₄, andconcentrated in vacuo. The crude product was purified by silica gelchromatography, eluting with a gradient of hexanes:EtOAc—100:0 to 80:20,to give the title compound. MS: m/z=345 (M+1).

Step D. (±)-Ethyl(4-amino-6-fluoro-2-oxo-2,3-dihydro-1H-indol-3-yl)acetate

A solution of (±)-4-ethyl 1-methyl2-(4-fluoro-2,6-dinitrophenyl)succinate from Step C (7.23 g, 21.0 mmol)and iron powder (5.86 g, 105 mmol) in EtOH (60 mL) and saturated aqueousNH₄Cl (15 mL) was stirred at reflux for 4.5 h. The warm reaction mixturewas filtered through Celite, rinsing the filter cake with ethyl acetate.The crude product solution was washed with saturated aqueous NaHCO₃ (300mL). The layers were separated and the aqueous layer was furtherextracted with EtOAc (2×200 mL). The combined organic layers were driedover Na₂SO₄, and concentrated in vacuo. The crude product was purifiedby silica gel chromatography, eluting with a gradient ofhexanes:EtOAc—100:0 to 50:50, to give the title compound. MS: m/z=253(M+1).

Step E. (±)-7-Fluoro-2a,5-dihydropolo[4,3,2-de]quinoline-2,4(1H,3)-dione

A solution of (±)-ethyl(4-amino-6-fluoro-2-oxo-2,3-dihydro-1H-indol-3-yl)acetate from Step D(3.28 g, 13.0 mmol) in degassed xylenes (100 mL) and AcOH (5 mL) washeated at reflux for 4.5 days, then allowed to slowly cool to ambienttemperature. The resulting precipitate was filtered, washing withhexanes, to give the title compound. MS: m/z=207 (M+1).

Step F.(±)-7-Fluoro-2a-methyl-2a,5-dihydropyrrolo[4,3,2-de]quinoline-2,4(1H,3H)-dione

To a stirred solution of(±)-7-fluoro-2a,5-dihydropyrrolo[4,3,2-de]quinoline-2,4(1H,3B)-dionefrom Step E (608 mg, 2.95 mmol) in degassed DMF (10 mL) at 0° C. wasadded sodium hydride (142 mg of a 60% dispersion in mineral oil, 3.54mmol). The mixture was stirred for 15 min, then iodomethane (0.184 mL,2.95 mmol) was added and stirring was continued for 1 h. The reactionmixture was poured onto H₂O (100 mL) and extracted with EtOAc (3×50 mL).The combined organic extracts were washed with H₂O (20 mL), dried overNa₂SO₄, filtered, and concentrated in vacuo. The crude product waspurified by silica gel chromatography, eluting with a gradient ofCH₂Cl₂:EtOAc—100:0 to 0:100, to give the title compound. MS: m/z=221(M+1).

Step G.7-Fluoro-2a-methyl-1,22a,5-tetrahydropyrrolo[4,3,2-de]quinolin-4(3-H)-oneenantiomer A

To a solution of(±)-7-fluoro-2a-methyl-2a,5-dihydropyrrolo[4,3,2-de]quinoline-2,4(1H,3B)-dionefrom Step F (340 mg, 1.54 mmol) in THF (10 mL) at 0° C. was addedDIBAL-H (7.72 mL of a 1 M solution in toluene, 7.72 mmol). The reactionmixture was stirred for 2 h and then quenched by the slow addition ofsaturated aqueous sodium potassium tartrate (100 mL) and extracted withEtOAc (3×50 mL). The combined organic extracts were washed with brine(20 mL), dried over Na₂SO₄, filtered, and concentrated in vacuo. Thecrude product was purified by silica gel chromatography, eluting with agradient of CH₂Cl₂:MeOH:NH₄OH—100:0:0 to 95:5:1, to give the racemictitle compound. The enantiomers were resolved by HPLC, utilizing aChiralPak AD column and eluting with MeOH. The first major peak to elutewas7-fluoro-2a-methyl-1,2,2a,5-tetrahydropyrrolo[4,3,2-de]quinolin-4(3H)-one,enantiomer A, the title compound, and the second major peak to elute was7-fluoro-2a-methyl-1,2,2a,5-tetrahydropyrrolo[4,3,2-de]quinolin-4(3)-one,enantiomer B. MS: m/z=207 (M+1).

(±)-2a,6-Dimethyl-1,2,2a,5-tetrahydropyrrolo[4,3,2-de]quinolin-4(3H)-oneStep A.(±)-2a-Methyl-1,2,2a,5-tetrahydropyrrolo[4,3,2-de]quinolin-4(3H)-one

Essentially following the procedures described for Intermediate 53 butusing 2-chloro-1,3-dinitrobenzene in place of2-chloro-5-fluoro-1,3-dinitrobenzene, the title compound was obtained.MS: m/z=189(M+1).

Step B.(±)-6-Bromo-2a-methyl-1,2,2a,5-tetrahydropyrrolo[4,3,2-de]quinolin-4(3H)-one

To a solution of(±)-2a-methyl-1,2,2a,5-tetrahydropyrrolo[4,3,2-de]quinolin-4(3H)-onefrom Step A (525 mg, 2.79 mmol) in CH₂Cl₂ (15 mL) at 0° C. was addedN-bromosuccinimide (496 mg, 2.79 mmol) and the mixture was allowed towarm slowly to ambient temperature. After 5 h, the reaction mixture wasquenched with saturated aqueous NaHCO₃ (10 mL) and extracted with EtOAc(150 mL). The organic layer was washed with brine, dried over Na₂SO₄,filtered, and concentrated in vacuo. The crude product was purified bysilica gel chromatography, eluting with a gradient of CH₂Cl₂:CH₃CN—100:0to 75:25, to give the title compound. MS: m/z=267 (M+1).

Step C.(±)-2a,6-Dimethyl-1,2,2a,5-tetrahydropyrrolo[4,3,2-de]quinolin-4(3H)-one

A mixture of(±)-6-bromo-2a-methyl-1,2,2a,5-tetrahydropyrrolo[4,3,2-de]quinolin-4(3H)-onefrom Step B (48 mg, 0.18 mmol), tetrakis(triphenylphosphine)palladium(0)(22 mg, 0.019 mmol), potassium carbonate (75 mg, 0.54 mmol), andtrimethylboroxine (0.126 mL of a 50 wt. % solution in THF, 0.50 mmol) in1,4-dioxane (0.9 mL) and H₂O (0.1 mL) was heated at 120° C. in amicrowave reactor for 40 min. The cooled reaction mixture was quenchedwith H₂O (5 mL) and extracted with EtOAc (20 mL). The organic layer waswashed with brine, dried over Na₂SO₄, filtered, and concentrated invacuo. The crude product was purified by silica gel chromatography,eluting with a gradient of CH₂Cl₂:MeOH—100:0 to 90:10, to give the titlecompound. MS: m/z=203 (M+1).

(±)-2a-Methyl-4-oxo-1,2,2a,3,4,5-hexahydropyrrolo[4,3,2-de]quinoline-6-carbonitrileStep A.(±)-2a-Methyl-4-oxo-1,2,2a,3,45-hexahydropyrrolo[4,3,2-de]quinoline-6-carbonitrile

A mixture of(±)-6-bromo-2a-methyl-1,2,2a,5-tetrahydropyrrolo[4,3,2-de]quinolin-4(30mL)-one (53 mg, 0.20 mmol, described in Intermediate 54),tetrakis(triphenylphosphine)palladium(0) (48 mg, 0.042 mmol), andcopper(I) cyanide (27 mg, 0.30 mmol) in DMF (2 mL) was heated at 150° C.for 3 h. The cooled reaction mixture was quenched with aqueous NaHCO₃(10 mL) and extracted with EtOAc (30 mL). The organic layer was washedwith brine, dried over Na₂SO₄, filtered, and concentrated in vacuo. Thecrude product was purified by silica gel chromatography, eluting with agradient of hexane:EtOAc—60:40 to 0:100, to give the title compound insufficient purity for use in the next step. MS: m/z=214 (M+1).

Example 1

(7R)-3′-Methyl-2-[(2a-methyl-2,4-dioxo-2a,3,4,5-tetrahydropyrrolo[4,3,2-de]quinolin-1(2H)-yl-methyl]-6,8-dihydro-2′H,5′H-spiro[cylopenta[g]quinoline-7,4′-imidazolidine]-2′,5′-dione,Diastereomer B

To a solution of2a-methyl-2a,5-dihydropyrrolo[4,3,2-de]quinoline-2,4(1H,3B)-dione,enantiomer B, (128 mg, 0.63 mmol, described in Intermediate 16) in DMF(1 mL), at 0° C., was added sodium hydride (60% dispersion in mineraloil; 28 mg, 0.70 mmol) and the resulting mixture was stirred for 30 min.A solution of(7R)-2-(chloromethyl)-3′-methyl-6,8-dihydro-2′H,5′H-spiro[cyclopenta[g]quinoline-7,4′-imidazolidine]-2′,5′-dione(100 mg, 0.32 mmol, described in Intermediate 14) in DMF (1 mL) wasadded dropwise and the resulting mixture was stirred at ambienttemperature for 2 h. The reaction mixture was quenched with a few dropsof TFA and purified directly by HPLC using a reversed phase C18 columnand eluting with a gradient of H₂O:CH₃CN:CF₃CO₂H—90:10:0.1 to 5:95:0.1.The pure, product-containing fractions were combined and poured intosaturated aqueous NaHCO₃ (10 mL). The mixture was extracted with CH₂Cl₂(3×10 mL). A precipitate was isolated from the organic layers byfiltration. The combined organic extracts were dried over Na₂SO₄,filtered, and concentrated in vacuo to give a residue. This residue wascombined with the filtered solid to give the title compound. MS: m/z=482(M+1). HRMS: m/z=482.1824; calculated m/z=482.1823 for C₂₇H₂₄NSO₄.

Example 2

(7R)-2-[(2,5-Dioxo-5,6-dihydro-4H-imidazo[1,5,4-de]quinoxalin-1(2H)-yl)methyl]-3′-methyl-6,8-dihydro-2′H,5′H-spiro[cyclopenta[g]quinoline-7,4′-imidazolidine]-2′,5′-dioneStep A. Methyl(3-{[(7R)-3′-methyl-2′,5′-dioxo-6,8-dihydrospiro[cyclopenta[g]quinoline-7,4-imidazolidin]-2-yl]methyl}-7-nitro-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl)acetate

To a solution of methyl(7-nitro-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl)acetate (68 mg, 0.27mmol, described in Intermediate 15) in DMF (1 mL), at 0° C., was addedsodium hydride (60% dispersion in mineral oil; 13 mg, 0.33 mmol) and theresulting mixture was stirred for 30 min. To the resulting mixture wasadded(7R)-2-(chloromethyl)-3′-methyl-6,8-dihydro-2H,5H-spiro[cyclopenta[g]quinoline-7,4′-imidazolidine]-2′,5′-dione(86 mg, 0.27 mmol, described in Intermediate 14) and stirring wascontinued at ambient temperature for 18 h. The reaction mixture wasquenched with a few drops of TFA and concentrated in vacuo to give thetitle compound in sufficient purity for use in the next step. MS:m/z=531 (M+1).

Step B. Methyl(7-amino-3-{[(7R)-3′-methyl-2′,5′-dioxo-6,8-dihydrospiro[cyclopenta[g]quinoline-7,4′-imidazolidin]-2-yl]methyl}-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl)acetate

A mixture of methyl(3-{[(7R)-3′-methyl-2′,5′-dioxo-6,8-dihydrospiro[cyclopenta[g]quinoline-7,4′-imidazolidin]-2-yl]methyl}-7-nitro-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl)acetatefrom Step A (143 mg, 0.27 mmol) and 10% Pd/C (20 mg) was stirredvigorously in MeOH (3 mL) and EtOAc (5 mL) under an atmosphere ofhydrogen (ca. 1 atm). Additional amounts of 10% Pd/C (20 mg) were addedafter 16 h and 24 h. After a total reaction time of 96 h, the mixturewas filtered through a pad of Celite, washing with MeOH, and thefiltrate was concentrated in vacuo to give the title compound insufficient purity for use in the next step. MS: m/z 501 (M+1).

Step C.(7R)-2-[(2,5-Dioxo-5,6-dihydro-4H-imidazo[1,5,4-de]quinoxalin-1(2H)-yl)methyl]-3′-methyl-6,8-dihydro-2′H,5′H-spiro[cyclopenta[g]quinoline-7,4′-imidazolidine]-2′,5′-dione

A mixture of methyl(7-amino-3-{[(7R)-3′-methyl-2′,5′-dioxo-6,8-dihydrospiro[cyclopenta[g]quinoline-7,4′-imidazolidin]-2-yl]methyl}-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl)acetatefrom Step B (135 mg, 0.27 mmol) and AcOH (1 mL) was heated in xylenes (5mL) at reflux for 3 h, then concentrated to dryness under reducedpressure. The crude product was partially purified by silica gelchromatography, eluting with a gradient of CH₂Cl₂:MeOH—100:0 to 90:10,to give a crude sample of the title compound. Further purification wasachieved by HPLC using a reversed phase C18 column and eluting with agradient of H₂O:CH₃CN:CF₃CO₂H—90:10:0.1 to 5:95:0.1. The pure,product-containing fractions were combined and concentrated to give thetitle compound. MS: m/z=469 (M+1). HRMS: m/z=469.1624; calculatedm/z=469.1619 for C₂₅H₂₁N₆O₄.

Example 3

(7R)-3′-Methyl-2-[(2a-methyl-4-oxo-2a,3,4,5-tetrahydropyrrolo[4,3,2-de]quinolin-1(2H)-yl)methyl]-6,8-dihydro-2′H,5′H-spiro[cyclopenta[g]quinoline-7,4′-imidazolidine]-2′,5′-dionediastereomer A

To a stirred solution of(7R)-3′-methyl-2′,5′-dioxo-6,8-dihydrospiro[cyclopenta[g]quinoline-7,4′-imidazolidine]-2-carbaldehyde(612 mg, 2.07 mmol, described in Intermediate 13),2a-methyl-1,2,2a,5-tetrahydropyrrolo[4,3,2-de]quinolin-4(3R)-one,enantiomer A, (300 mg, 1.59 mmol, described in Intermediate 19), andAcOH (0.46 mL, 7.97 mmol) in DCE (5 mL) was added sodiumtriacetoxyborohydride (507 mg, 2.39 mmol) and the mixture was stirredfor 90 min at ambient temperature. The reaction mixture was partitionedbetween saturated aqueous NaHCO₃ (30 mL) and CH₂Cl₂ (30 mL). The organiclayer was removed and the aqueous layer was extracted further withCH₂Cl₂ (3×30 mL). The combined organic extracts were dried over Na₂SO₄,filtered, and concentrated in vacuo. The crude product was purified bysilica gel chromatography, eluting with a gradient of CH₂Cl₂:MeOH—100:0to 95:5, to give the title compound. MS: m/z=468 (M+1). HRMS:m/z=468.2032; calculated m/z=468.2030 for C₂₇H₂₆N₅O₃.

Example 4

(7R)-2-[(2,4-Dioxo-4,5-dihydropyrrolo[4,3,2-de]quinolin-1(2H)-yl)methyl]-3′-methyl-6,8-dihydro-2′H,5′H-spiro[cyclopenta[g]quinoline-7,4′-imidazolidine]-2′,5′-dione

Essentially following the procedures described for Example 1, but usingpyrrolo[4,3,2-de]quinoline-2,4(1H,5B)-dione (described in Intermediate17) in place of2a-methyl-2a,5-dihydropyrrolo[4,3,2-de]quinoline-2,4(1H,3H)-dione,enantiomer B, the title compound and its isomer were prepared. The crudeproduct was purified by HPLC using a reversed phase C18 column andeluting with a gradient of H₂O:CH₃CN:CF₃CO₂H—90:10:0.1 to 5:95:0.1 togive a mixture of the two isomeric products. Further purification wasachieved by silica gel chromatography, eluting with a gradient ofCH₂Cl₂:acetone—100:0 to 50:50, to give(7R)-2-[(2,4-dioxo-2,4-dihydropyrrolo[4,3,2-de]quinolin-5(1H)-yl(methyl]-3′-methyl-6,8-dihydro-2′H,5′H-spiro[cyclopenta[g]quinoline-7,4′-imidazolidine]-2′,5′-dione,which eluted first, and(7R)-2-[(2,4-dioxo-4,5-dihydropyrrolo[4,3,2-de]quinolin-1(2H)-yl)methyl]-3′-methyl-6,8-dihydro-2′H,5′H-spiro[cyclopenta[g]quinoline-7,4′-imidazolidine]-2′,5′-dione,the title compound, which eluted second. MS: m/z=466 (M+1). HRMS:m/z=466.1508; calculated m/z 466.1510 for C₂₆H₂₀N₅O₄.

Example 5

(7R)-2-[(2,4-Dioxo-2,4-dihydropyrrolo[4,3,2-de]quinolin-5(1H)-yl)methyl]-3′-methyl-6,8-dihydro-2′H,5′H-spiro[cyclopenta[g]quinoline-7,4′-imidazolidine]-2′,5′-dione

The title compound was isolated from the same reaction mixture as theproduct in Example 4. MS: m/z=466 (M+1). HRMS: m/z=466.1512; calculatedm/z=466.1510 for C₂₆H₂₀N₅O₄.

Example 6

(7R)-3′-Methyl-2-[(2a-methyl-4-oxo-2a,3,4,5-tetrahydropyrrolo[4,3,2-de]quinolin-1(2H)-yl)methyl]-9-bromo-6,8-dihydro-2′H,5′H-spiro[cyclopenta[g]quinoline-7,4′-imidazolidine]-2′,5′-dione,Diastereomer A

Essentially following the procedures described for Example 3, but using(7R)-9-bromo-3′-methyl-2′,5′-dioxo-6,8-dihydrospiro[cyclopenta[g]quinoline-7,4′-imidazolidine]-2-carbaldehyde(described in Intermediate 21) in place of(7R)-3′-methyl-2′,5′-dioxo-6,8-dihydrospiro[cyclopenta[g]quinoline-7,4′-imidazolidine]-2-carbaldehyde,the title compound was prepared. MS: m/z=546 (M+1). HRMS: m/z=546.1176;calculated m/z=546.1136 for C₂₇H₂₅ ⁷⁹BrN₅O₃.

Examples 7-8

Essentially following the procedures outlined for Example 1 thecompounds listed in Table 1 were prepared. The requisite amines werecommercially available, described in the literature, synthesizedaccording to methodology described herein (vide supra), or readilysynthesized by one skilled in the art of organic synthesis. In somecases, straightforward protecting group strategies were applied.

TABLE 1

Example R^(b) MS (M + 1) 7

483 8

551

Examples 9-32

Essentially following the procedures outlined for Example 3 thecompounds listed in Table 2 were prepared. The requisite amines werecommercially available, described in the literature, synthesizedaccording to methodology described herein (vide supra), or readilysynthesized by one skilled in the art of organic synthesis. In somecases, straightforward protecting group strategies were applied. Theproduct of the reductive alkylation was manipulated further using knownmethodology to afford some of the compounds in Table 2.

TABLE 2

Example R^(b) MS (M +1) 9

454 10

540 11

512 12

539 13

565 14

518 15

482 16

502 17

482 18

508 19

500 20

512 21

535 22

536 23

493 24

546 25

482 26

583 27

483 28

579 29

554 30

551 31

567 32

583

Example 33

[1-{[(7R-3′-Methyl-2′,5′-dioxo-6,8-dihydrospiro[cyclopenta[g]quinoline-7,4′-imidazolidin]-2-yl]methyl}-4-oxo-1,2,4,5-tetrahydropyrrolo[4,3,2-de]quinolin-2a(3H)-yl]aceticAcid, Diastereomer A

To a stirred solution of ethyl[1-{[(7R)-3′-methyl-2′,5′-dioxo-6,8-dihydrospiro[cyclopenta[g]quinoline-7,4′-imidazolidin]-2-yl]methyl}-4-oxo-1,2,4,5-tetrahydropyrrolo[4,3,2-de]quinolin-2a(3H)-yl]acetate,diastereomer A (200 mg, 0.371 mmol, described in Example 10) in THF (7mL) and H₂O (7 mL) was added 1 N LiOH (0.93 mL, 0.93 mmol) and themixture was stirred at ambient temperature for 18 h. The mixture wasadjusted to ca. pH 3 by addition of 10% aqueous citric acid andextracted with EtOAc (50 mL). The organic layer was dried over Na₂SO₄,filtered, and concentrated to dryness in vacuo to give the titlecompound. MS: m/z=512 (M+1). HRMS: m/z=512.1899; calculated m/z=512.1929for C₂₈H₂₆N₅O₅.

Example 34

(7R)-3′-methyl-2-{[4-oxo-2a-(2-oxo-2-pyrrolidin-1-ylethyl)-2a,3,4,5-tetrahydropyrrolo[4,3,2-de]quinolin-1(2H)-yl]methyl}-6,8-dihydro-2′H,5′H-spiro[cyclopenta[g]quinoline-7,4′-imidazolidine]-2′,5′-dione,Diastereomer A

A mixture of[1-{[(7R)-3′-methyl-2′,5′-dioxo-6,8-dihydrospiro[cyclopenta[g]quinoline-7,4′-imidazolidin]-2-yl]methyl}-4-oxo-1,2,4,5-tetrahydropyrrolo[4,3,2-de]quinolin-2a(3H)-yl]aceticacid, diastereomer A (50 mg, 0.098 mmol, described in Example 33),pyrrolidine (20 mg, 0.282 mmol), EDC (28 mg, 0.147 mmol), HOBT (22 mg,0.147 mmol), and N,N-diisopropylethylamine (0.051 mL, 0.293 mmol) wasstirred in DMF (0.5 mL) at ambient temperature for 18 h. The reactionmixture was partitioned between saturated aqueous NaHCO₃ (20 mL) andCH₂Cl₂ (10 mL). The organic layer was removed and the aqueous layer wasextracted further with CH₂Cl₂ (2×10 mL). The combined organic extractswere washed with brine (10 mL), dried over Na₂SO₄, filtered, andconcentrated in vacuo. The crude product was purified by silica gelchromatography, eluting with a gradient of CH₂Cl₂:MeOH—100:0 to 90:10,to give the title compound. MS: m/z=565 (M+1). HRMS: m/z=565.2578;calculated m/z=565.2558 for C₃₂H₃₃N₆O₄.

Example 35

(±)-3′-Methyl-2-[(4-oxo-2a,3,4,5-tetrahydropyrrolo[4,3,2-de]quinolin-1(2H)-yl)carbonyl]-6,8-dihydro-2′H,5′H-spiro[cyclopenta[g]quinoline-7,4′-imidazolidine]-2′,5′-dione,Diastereomer B

A mixture of(±)-3′-methyl-2′,5′-dioxo-6,8-dihydrospiro[cyclopenta[g]quinoline-7,4′-imidazolidine]-2-carboxylicacid (14 mg, 0.045 mmol, described in Intermediate 25),1,2,2a,5-tetrahydropyrrolo[4,3,2-de]quinolin-4(3H)-one, enantiomer B (8mg, 0.045 mmol, described in Intermediate 18), EDC (13 mg, 0.068 mmol),HOBT (9 mg, 0.068 mmol), and NAN-diisopropylethylamine (0.039 mL, 0.226mmol) is stirred in DMF (0.7 mL) at ambient temperature for 18 h. Thereaction mixture is purified directly by HPLC using a reversed phase C18column and eluting with a gradient of H₂O:CH₃CN:CF₃CO₂H—90:10:0.1 to5:95:0.1. The pure, product-containing fractions are combined andconcentrated to give the title compound.

Example 36

3′-Methyl-2-[(4-oxo-2a,3,4,5-tetrahydropyrrolo[4,3,2-de]quinolin-1(2H)-yl)methyl]-6,8-dihydro-2′H5′H-spiro[cyclopenta[g]quinoxaline-7,4′-imidazolidine]-2′,5′-dione,diastereomers A & B Step A.(±)-2-(Hydroxymethyl)-3′-methyl-6,8-dihydro-2′H5′H-spiro[cyclopenta[g]quinoxaline-7,4′-imidazolidine]-2′,5′-dione

To a stirred solution of5′,6′-diamino-3-methyl-spiro[imidazolidine-4,2′-indane]-2,5-dione (295mg, 1.20 mmol, described in Intermediate 22) and MgSO₄ (1.06 g, 8.81mmol) in CH₂Cl₂ (15 mL) and CH₃OH (15 mL) is added the ethanolate ofhydroxypyruvic aldehyde trimer [Evans et al., J. Am. Chem. Soc. 1938,60, 1628-1629] (320 mg, 1.0 mmol). After 4 h, more of the ethanolate ofhydroxypyruvic aldehyde trimer (340 mg, 1.1 mmol) is added and themixture is heated to reflux for 2 h. The reaction mixture is partitionedbetween brine (50 mL) and EtOAc (150 mL). The organic layer is removedand the aqueous layer is extracted further with EtOAc (2×100 mL). Thecombined organic extracts are dried over Na₂SO₄, filtered, andconcentrated in vacuo. The crude product is purified by silica gelchromatography, eluting with a gradient of CH₂Cl₂:MeOH—100:0 to 90:10,to give the title compound.

Step B.(±)-3′-Methyl-2′,5-dioxo-6,8-dihydrospiro[cyclopenta[g]quinoxaline-7,4′-imidazolidine]-2-carbaldehyde

A mixture of(±)-2-(hydroxymethyl)-3′-methyl-6,8-dihydro-2′H,5′H-spiro[cyclopenta[g]quinoxaline-7,4′-imidazolidine]-2′,5′-dionefrom Step A (33 mg, 0.11 mmol) and manganese (IV) oxide (158 mg, 1.82mmol) in CHCl₃ (5 mL) and MeOH (0.1 mL) is heated at reflux for 18 h.The cooled mixture is filtered through a pad of Celite, washing withCH₂Cl₂ and MeOH, and the filtrate is concentrated in vacuo to give thetitle compound.

Step C.3′-Methyl-2-[(4-oxo-2a,3,4,5-tetrahydropyrrolo[4,3,2-de]quinolin-1(2B)-yl)methyl]-6,8-dihydro-2′H,5′H-spiro[cyclopenta[g]quinoxaline-7,4′-imidazolidine]-2′,5′-dione,Diastereomers A & B

To a stirred solution of(±)-3′-methyl-2′,5′-dioxo-6,8-dihydrospiro[cyclopenta[g]quinoxaline-7,4′-imidazolidine]-2-carbaldehydefrom Step B (15 mg, 0.051 mmol),1,2,2a,5-tetrahydropyrrolo[4,3,2-de]quinolin-4(3H)-one, enantiomer B (11mg, 0.061 mmol, described in Intermediate 18), and AcOH (0.029 mL, 0.51mmol) in DCE (0.4 mL) is added sodium triacetoxyborohydride (16 mg,0.076 mmol) and the mixture is stirred for 4 h at ambient temperature.The solvent is removed in vacuo and the residue is purified by HPLCusing a reversed phase C18 column and eluting with a gradient ofH₂O:CH₃CN:CF₃CO₂H—90:10:0.1 to 5:95:0.1. Saturated aqueous NaHCO₃ (1 mL)is added to the tubes in the fraction collector in order to rapidlyneutralize to eluted solvent. The pure, product-containing fractions arecombined and extracted with CH₂Cl₂, and the organic extract is dried(Na₂SO₄), filtered, and concentrated in vacuo to give the titlecompound.

Example 37

2′-[(2,5-Dioxo-5,6-dihydro-4H-imidazo[1,5,4-de]quinoxalin-1(2H)-yl)methyl]-3-methyl-5′,7′-dihydro-1′H2H,5H-spiro[imidazolidine-4,6′-indeno[5,6-d]imidazole]-2,5-dione

A mixture of5′,6′-diamino-3-methyl-spiro[imidazolidine-4,2′-indane]-2,5-dione (27mg, 0.11 mmol, described in Intermediate 22), sodium(2,5-dioxo-5,6-dihydro-4H-imidazo[1,5,4-de]quinoxalin-1(2H)-yl)acetate(27 mg, 0.10 mmol, described in Intermediate 31), BOP (50 mg, 0.11mmol), and N,N-diisopropylethylamine (0.019 mL, 0.1 mmol) is stirred inDMF (0.4 mL) at ambient temperature for 2 h, then AcOH (0.4 mL) is addedand the resulting mixture is heated to 60° C. for 18 h. The mixture isallowed to cool and the precipitate is isolated by filtration. Thissolid is washed with H₂O, then MeOH, then CH₂Cl₂, then dried in vacuo togive the title compound.

Example 38

(±)-3-Methyl-2′-[(6-methyl-2,5-dioxo-5,6-dihydro-4H-imidazo[1,5,4-de]quinoxalin-1(2H)-yl)methyl]-4′,5′,7′,9′-tetrahydro-1′H,2H,5H-spiro[imidazolidine-4,8′-indeno[5,6-d][1,3]diazepine]-2,5-dioneStep A.(6-Methyl-2,5-dioxo-5,6-dihydro-4H-imidazo[1,5,4-de]quinoxalin-1(2H)-yl)acetonitrile

To a stirred solution of6-methyl-4H-imidazo[1,5,4-de]quinoxaline-2,5(1H,6H)-dione (296 mg, 1.46mmol, described in Intermediate 28) in DMF (5 mL) at 0° C. was addedsodium hydride (60% dispersion in mineral oil; 78 mg, 1.96 mmol) and theresulting mixture was stirred for 5 min. Bromoacetonitrile (0.122 mL,1.75 mmol) in was added dropwise and the reaction mixture was allowed towarm to ambient temperature and was stirred for 3 h, then quenched withH₂O (20 mL). The mixture was extracted with EtOAc (2×30 mL) and thecombined organic extracts were washed with brine (10 mL), then driedover Na₂SO₄, filtered, and concentrated in vacuo. The crude product waspartially purified by silica gel chromatography, eluting with a gradientof CH₂Cl₂:MeOH—100:0 to 95:5, followed by trituration with CH₂Cl₂ togive the title compound. MS: m/z=243 (M+1).

Step B.1-Ethoxy-2-(6-methyl-2,5-dioxo-5,6-dihydro-4H-imidazo[1,5,4-de]quinoxalin-1(2H)-yl)ethaniminiumChloride

A suspension of(6-methyl-2,5-dioxo-5,6-dihydro-4H-imidazo[1,5,4-de]quinoxalin-1(2B)-yl)acetonitrilefrom Step A (54 mg, 0.223 mmol) in EtOH (5 mL) was cooled to 0° C., thenHCl (g) was bubbled in slowly for 1 min. The resulting solution was agedfor 30 min, then concentrated to dryness in vacuo to give the titlecompound in sufficient purity for use in the next step. MS: m/z=290(M+2).

Step C.(±)-3-Methyl-2′-[(6-methyl-2,5-dioxo-5,6-dihydro-4H-imidazo[1,5,4-de]quinoxalin-1(2H)-yl)methyl]-4′,5′,7′,9′-tetrahydro-1′H,2H,5H-spiro[imidazolidine-4,8′-indeno[5,6-d][1,3]diazepine]-2,5-dione

A mixture of1-ethoxy-2-(6-methyl-2,5-dioxo-5,6-dihydro-4H-imidazo[1,5,4-de]quinoxalin-1(2H)-yl)ethaniminiumchloride from Step B (72 mg, 0.22 mmol) and(±)-5′-amino-6′-(2-aminoethyl)-3-methyl-1′,3′-dihydro-2H,5H-spiro[imidazolidine-4,2′-indene]-2,5-dione(68 mg, 0.25 mmol, described in Intermediate 27) in EtOH (7 mL) isheated to 100° C. for 5 min then allowed to cool. The reaction is pouredinto dilute aqueous NaHCO₃ (50 mL) and the mixture is extracted withEtOAc (100 mL). The organic layer is washed with brine, dried overNa₂SO₄, filtered, and concentrated under reduced pressure. The crudeproduct is purified by silica gel chromatography, eluting with agradient of CH₂Cl₂:MeOH—100:0 to 80:20, to give the title compound.

Examples 39-40

Essentially following the procedures outlined for Example 3 thecompounds listed in Table 3 are prepared. The requisite amines arecommercially available, described in the literature, synthesizedaccording to methodology described herein (vide supra), or readilysynthesized by one skilled in the art of organic synthesis. In somecases, straightforward protecting group strategies are applied.

TABLE 3

Example R^(b) 39

40

Examples 41-53

Essentially following the procedures outlined for Example 37 thecompounds listed in Table 4 are prepared. The requisite acids arecommercially available, described in the literature, synthesizedaccording to methodology described herein (vide supra), or readilysynthesized by one skilled in the art of organic synthesis. In somecases, straightforward protecting group strategies are applied.

TABLE 4

Example R^(c) 41

42

43

44

45

46

47

48

49

50

51

52

53

Examples 54-57

Essentially following the procedures outlined for Example 3 thecompounds listed in Table 5 were prepared. The requisite amines werecommercially available, described in the literature, synthesizedaccording to methodology described herein (vide supra), or readilysynthesized by one skilled in the art of organic synthesis. In somecases, straightforward protecting group strategies were applied. Theproduct of the reductive alkylation was manipulated further using knownmethodology to afford some of the compounds in Table 5.

TABLE 5

Example R^(b) MS (M + 1) 54

569 55

555 56

582 57

498

While the invention has been described and illustrated with reference tocertain particular embodiments thereof, those skilled in the art willappreciate that various adaptations, changes, modifications,substitutions, deletions, or additions of procedures and protocols maybe made without departing from the spirit and scope of the invention.For example, effective dosages other than the particular dosages as setforth herein above may be applicable as a consequence of variations inthe responsiveness of the mammal being treated for any of theindications with the compounds of the invention indicated above.Likewise, the specific pharmacological responses observed may varyaccording to and depending upon the particular active compounds selectedor whether there are present pharmaceutical carriers, as well as thetype of formulation and mode of administration employed, and suchexpected variations or differences in the results are contemplated inaccordance with the objects and practices of the present invention. Itis intended, therefore, that the invention be defined by the scope ofthe claims which follow and that such claims be interpreted as broadlyas is reasonable.

1. A compound of the formula I:

wherein: A¹, A² and A³ are each independently selected from: (1) a bond,(2) —CR¹³R¹⁴—, wherein R¹³ and R¹⁴ are each independently selected from:(a) hydrogen, (b) C₁₋₆ alkyl, which is unsubstituted or substituted with1-5 substituents each independently selected from: (i) —C₃₋₆cycloalkyl,(ii) —O—C₁₋₆alkyl, (iii) halo, (iv) hydroxy, and (v) phenyl, (c)hydroxy, and (d) halo, (3) —NR¹⁰—, (4) —CR¹³R¹⁴—NR¹⁰—, (5)—CR¹³R¹⁴—CH₂—, (6) —CH₂—CR¹³R¹⁴—, (7) —O—C R¹³R¹⁴—, (8) —C R¹³R¹⁴—O—,(9) —C≡C—, (10) —C(R¹³)═C(R¹⁴)—, and (11) —C(═O)—, where one or two ofA¹, A² and A³ are optionally absent; 0-1 of A⁴, A⁵, A⁶ and A⁷ isselected from: (1) —O—, (2) —C(═O)— (3) —N(R¹⁵)—, wherein R¹⁵ isselected from: (i) hydrogen, (ii) C₁₋₆ alkyl, which is unsubstituted orsubstituted with 1-5 substituents where the substituents are eachindependently selected from: (a) hydroxy, (b) —O—C₁₋₆alkyl, (c) halo,(d) —C₃₋₆cycloalkyl, (e) trifluoromethyl, and (f) phenyl, where theremainder of A⁴, A⁵, A⁶ and A⁷ are each independently selected from: (1)a bond, and (2) —CR¹³R¹⁴—, where one or both of A⁴ and A⁷ are optionallyabsent; B¹ and B⁴ are each independently selected from: (1)

(2)

and (3)

B² and B³ are each independently selected from: (1) a bond (2) ═C(R¹)—,(3) —C R¹R²—, (4) —C(═O)—, (5) —C(═S)—, (6) —C(═NR¹)—, (7) ═N—, (8)—N(R¹)—, (9) —O—, (10) —S—, and (11) —SO₂—, where one of B² and B³ isoptionally absent; D¹ and D² are each independently selected from: (1)═C(R¹)—, (2) —C R¹R²—, (3) —C(═O)—, (4) —C(═S)—, (5) ═N—, (6) —N(R¹)—,(7) —O—, (8) —S—, (9) —SO₂—, and (10) —C(═NR¹)—; E¹ and E⁵ are eachindependently selected from: (1) ═C(R⁴)—, (2) —C R⁴R⁵—, (3) —C(═O)—, (4)—C(═S)—, (5) ═N—, (6) ═N⁺(O—)—, (7) —N(R⁴)—, (8) —O—, (9) —S—, and (10)—SO₂—; E³ and E⁴ are each independently selected from: (1) a bond, (2)═C(R⁴)—, (3) —C R⁴R⁵—, (4) —C(═O)—, (5) ═N—, (6) ═N⁺(O—)—, (7) —N(R⁴)—,and (8) —O—, where one or both of E³ and E⁴ are optionally absent; E² isselected from: (1)

(2)

and (3)

G¹ and G² are each independently selected from: (1) ═C(R⁴)—, (2) ═N—,and (3)=N⁺(O—)—; T, U and V are each independently selected from: (1)═C(R¹)—, and (2) ═N—, and (3) ═N⁺(O—)—; wherein at least one of T, U,and V is ═C(R¹)—; W, X, Y, and Z are each independently selected from:(1) a bond (2) ═C(R¹)—, (3) —C R¹R²—, (4) —C(═O)—, (5) —C(═S)—, (6) ═N—,(7) —N(R¹)—, (8) —O—, (9) —S—, (10) —S(O)—, (11) —SO₂—, and (12)—C(═NR¹)—; where 1-4 of W, X, Y and Z are optionally absent; R¹ and R²are each independently selected from: (1) hydrogen; (2) —C₁₋₆alkyl,which is unsubstituted or substituted with 1-7 substituents eachindependently selected from: (a) halo, (b) hydroxy, (c) —O—C₁₋₆alkyl,which is unsubstituted or substituted with 1-5 halo, (d)—C₃₋₆cycloalkyl, (e) phenyl or heterocycle, wherein heterocycle isselected from: azetidinyl, azepanyl, imidazolyl, oxazolyl, pyridinyl,pyrimidinyl, pyrazinyl, pyridazinyl, piperidinyl, azepinyl, piperazinyl,pyrazolyl, pyrrolidinyl, thiazolyl, thienyl, triazolyl, tetrazolyl,tetrahydrofuryl, or morpholinyl, which phenyl or heterocycle isunsubstituted or substituted with 1-5 substituents each independentlyselected from: (i) —C₁₋₆alkyl, which is unsubstituted or substitutedwith 1-5 halo, (ii) —O—C₁₋₆alkyl, which is unsubstituted or substitutedwith 1-5 halo, (iii) halo, (iv) hydroxy, (v) oxo, (vi) amino (vii)phenyl, and (viii) benzyl (f) —CO₂R⁹, wherein R⁹ is independentlyselected from: (i) hydrogen, (ii) —C₁₋₆alkyl, which is unsubstituted orsubstituted with 1-6 substituents, substituents each independentlyselected from: (I) halo, (II) hydroxy, (III) —O—C₁₋₆alkyl, which isunsubstituted or substituted with 1-5 halo, (IV) —C₃₋₆cycloalkyl, (V)phenyl, which is unsubstituted or substituted with 1-5 substituents eachindependently selected from:  (1) —C₁₋₄alkyl,  (2) —O—C₁₋₆alkyl,  (3)halo,  (4) trifluoromethyl, and  (5) —OCF₃, (iii) —C₃₋₆cycloalkyl, whichis unsubstituted or substituted with 1-5 halo, and (iv) phenyl orheterocycle, wherein heterocycle is selected from: pyridinyl,pyrimidinyl, pyrazinyl, pyridazinyl, thienyl, pyrrolidinyl, thiazolyl,oxazolyl, imidazolyl, triazolyl, tetrazolyl, benzimidazolyl,benzothiazolyl, benzoxazolyl, imidazolinyl, indolinyl, indolyl,quinolinyl, isoquinolinyl, tetrahydroquinolinyl, isoindolinyl,tetrahydroisoquinolinyl, tetrahydrofuryl, quinoxalinyl, piperidinyl,piperazinyl, and morpholinyl, which phenyl or heterocycle isunsubstituted or substituted with 1-5 substituents each independentlyselected from: (I) halo, (II) —C₁₋₆alkyl, which is unsubstituted orsubstituted with 1-5 halo (III) —O—C₁₋₆alkyl, which is unsubstituted orsubstituted with 1-5 halo (IV) —C₃₋₆cycloalkyl, (V) oxo, (VI) —CN, (VII)hydroxy, and (VIII) phenyl, (g) —NR¹⁰R¹¹, wherein R¹⁰ and R¹¹ are eachindependently selected from: (i) hydrogen, (ii) —C₁₋₆alkyl, which isunsubstituted or substituted with 1-6 substituents each independentlyselected from: (I) —O—C₁₋₆alkyl, (II) halo, (III) hydroxy, (IV) —OCF₃,(V) —C₃₋₆cycloalkyl, and (VI) phenyl, (iii) —C₄₋₆cycloalkyl, (iv)phenyl, which is unsubstituted or substituted with 1-5 substituentswhere the substituents are independently selected from: (I)—C₁₋₆alkyl,(II) —O—C₁₋₆alkyl, (III) halo, (IV) hydroxy, (V) trifluoromethyl, (VI)—OCF₃, and (VII) CN, and (v) benzyl, which is unsubstituted orsubstituted with 1-5 substituents where the substituents areindependently selected from: (I) —C₁₋₆alkyl, (II) —O—C₁₋₆alkyl, (III)halo, and (IV) trifluoromethyl, (vi) —COR⁹, and (vii) —SO₂R¹², (h)—SO₂R¹², wherein R¹² is selected from: (i) —C₁₋₆alkyl, which isunsubstituted or substituted with 1-6 fluoro, (ii) —C₃₋₆cycloalkyl,(iii) phenyl or heterocycle, wherein heterocycle is selected from:pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, piperidinyl,piperazinyl, pyrrolidinyl, thienyl, or morpholinyl, which phenyl orheterocycle is unsubstituted or substituted with 1-5 substituentsindependently selected from: (I) —C₁₋₆alkyl, (II) —O—C₁₋₆alkyl, (III)halo, (IV) hydroxy, (V) trifluoromethyl, (VI) —OCF₃, and (VII) CN, and(iv) benzyl, which is unsubstituted or substituted with 1-5 substituentsindependently selected from: (I) —C₁₋₆alkyl, (II) —O—C₁₋₆alkyl, (III)halo, and (IV) trifluoromethyl, (i) —CONR^(10a)R^(11a), wherein R^(10a)and R^(11a) are each independently selected from: (i) hydrogen, (ii)—C₁₋₆alkyl, which is unsubstituted or substituted with 1-6 substituentseach independently selected from: (I) —O—C₁₋₆alkyl, which isunsubstituted or substituted with 1-5 halo, (II) halo, (III) hydroxy,(IV) —OCF₃, (V) —C₃₋₆cycloalkyl, and (VI) phenyl, (iii) —C₅₋₆cycloalkyl,(iv) phenyl, which is unsubstituted or substituted with 1-5 substituentswhere the substituents are independently selected from: (I) —C₁₋₆alkyl,which is unsubstituted or substituted with 1-5 halo, (II) —O—C₁₋₆alkyl,which is unsubstituted or substituted with 1-5 halo, (III) halo, (IV)hydroxy, (V) trifluoromethyl, (VI) —OCF₃, and (VII) CN, and (v) benzyl,which is unsubstituted or substituted with 1-5 substituents where thesubstituents are independently selected from: (I) —C₁₋₆alkyl, which isunsubstituted or substituted with 1-5 halo, (II) —O—C₁₋₆alkyl, which isunsubstituted or substituted with 1-5 halo, (III) halo, and (IV)trifluoromethyl, or where R^(10a) and R^(11a) join to form a ringselected from azetidinyl, pyrrolidinyl, piperidinyl, azepanyl,piperazinyl, or morpholinyl, which ring is unsubstituted or substitutedwith 1-5 substituents each independently selected from: (I) —C₁₋₆alkyl,which is unsubstituted or substituted with 1-5 halo, (II) —O—C₁₋₆alkyl,which is unsubstituted or substituted with 1-5 halo, (III) halo, (IV)hydroxy, (V) phenyl, (VI) benzyl, (VII) —COR⁹, and (VIII) —SO₂R¹² (j)trifluoromethyl, (k) —OCO₂R⁹, (l) —(NR^(10a))CO₂R⁹, (m)—O(CO)NR^(10a)R^(11a), (n) —(NR⁹)(CO)NR^(10a)R^(11a), (o)—O—C₃₋₆cycloalkyl, (p) —SO₂NR^(10a)R^(11a), and (q) —CN, (3)—C₃₋₆cycloalkyl, which is unsubstituted or substituted with 1-7substituents each independently selected from: (a) halo, (b) hydroxy,(c) —O—C₁₋₆alkyl, which is unsubstituted or substituted with 1-5 halo,(d) —C₁₋₆alkyl, which is unsubstituted or substituted with 1-5 halo, (e)phenyl, which is unsubstituted or substituted with 1-5 substituents eachindependently selected from: (i) —C₁₋₆alkyl, (ii) —O—C₁₋₆alkyl, (iii)halo, (iv) hydroxy, and (v) trifluoromethyl, (4) phenyl or heterocycle,wherein heterocycle is selected from: pyridinyl, pyrimidinyl, pyrazinyl,thienyl, pyridazinyl, pyrrolidinyl, azetidinyl, azepanyl, thiazolyl,isothiazolyl, oxazolyl, isoxazolyl, imidazolyl, triazolyl, tetrazolyl,azepinyl, benzimidazolyl, benzopyranyl, benzofuryl, benzothiazolyl,benzoxazolyl, chromanyl, furyl, imidazolinyl, indolinyl, indolyl,quinolinyl, isoquinolinyl, tetrahydroquinolinyl, isoindolinyl,tetrahydroisoquinolinyl, 2-oxopiperazinyl, 2-oxopiperidinyl,2-oxopyrrolidinyl, pyrazolidinyl, pyrazolyl, pyrrolyl, quinazolinyl,tetrahydrofuryl, thiazolinyl, purinyl, naphthyridinyl, quinoxalinyl,1,3-dioxolanyl, oxadiazolyl, piperidinyl, tetrahydropyranyl,tetrahydrothienyl, tetrahydrothiopyranyl, and morpholinyl, which phenylor heterocycle is unsubstituted or substituted with 1-5 substituentseach independently selected from: (a) —C₁₋₆alkyl, which is unsubstitutedor substituted with 1-5 substituents where the substituents are eachindependently selected from: (i) halo, (ii) hydroxy, (iii) —O—C₁₋₆alkyl,which is unsubstituted or substituted with 1-5 halo, (iv)—C₃₋₆cycloalkyl, (v) phenyl, (vi) —CO₂R⁹, and (vii) —NR¹⁰R¹¹, (b) halo,(c) hydroxy, (d) —O—C₁₋₆alkyl, which is unsubstituted or substitutedwith 1-6 fluoro, (e) —C₃₋₆cycloalkyl, (f) phenyl or heterocycle, whereinheterocycle is selected from: pyrrolidinyl, piperidinyl, piperazinyl,pyridinyl, pyrimidinyl, pyrazinyl, thienyl, or morpholinyl, which phenylor heterocycle is unsubstituted or substituted with 1-5 substituentseach independently selected from: (i) —C₁₋₆alkyl, which is unsubstitutedor substituted with 1-5 halo, (ii) —O—C₁₋₆alkyl, which is unsubstitutedor substituted with 1-5 halo, (iii) halo, (iv) hydroxy, and (v)trifluoromethyl, (g) —CO₂R⁹, (h) —(CO)R⁹, (i) —NR¹⁰R¹¹, (j)—CONR^(10a)R^(11a), (k) oxo (l) —SR¹², (m) —S(O)R¹², (n) —SO₂R¹², (o)—CN and (p) —SO₂NR^(10a)R^(11a), (5) halo, (6) oxo, (7) hydroxy, (8)—O—C₁₋₆alkyl, which is unsubstituted or substituted with 1-5substituents where the substituents are each independently selectedfrom: (a) halo, (b) hydroxy, (c) —C₃₋₆cycloalkyl, (d) phenyl, (e)—CO₂R⁹, and (f) —NR¹⁰R¹¹, (9) —CN, (10) —CO₂R⁹, (11) —NR¹⁰R¹¹, (12)—SR¹², (13) —S(O)R¹², (14) —SO₂R¹², (15) —SO₂NR^(10a)R^(11a), (16)—CONR^(10a)R^(11a), (17) —OCO₂R⁹, (18) —(NR^(10a))CO₂R⁹, (19)—O(CO)NR^(10a)R^(11a), (20) —(NR⁹)(CO)NR^(10a)R¹¹a, (21)—(CO)—(CO)NR^(10a)R^(11a), and (22) —(CO)—(CO)OR⁹; R⁴ and R⁵ are eachindependently selected from: (1) hydrogen; (2) —C₁₋₄alkyl, which isunsubstituted or substituted with 1-5 substituents each independentlyselected from: (a) halo, (b) hydroxy, (c) —O—C₁₋₆alkyl, which isunsubstituted or substituted with 1-5 halo, (d) —C₃₋₆cycloalkyl, (e)phenyl, (f) —CO₂R⁹, (g) —NR¹⁰R¹¹, and (h) —CONR^(10a)R^(11a) (3)—C₃₋₆cycloalkyl, (4) phenyl, which is unsubstituted or substituted with1-3 substituents where the substituents are each independently selectedfrom: (a) —C₁₋₄alkyl, which is unsubstituted or substituted with 1-3halo, (b) halo, (c) hydroxy, and (d) —O—C₁₋₄alkyl, which isunsubstituted or substituted with 1-6 halo, (5) halo, (6) hydroxy, (7)—O—C₁₋₆alkyl, which is unsubstituted or substituted with 1-5 halo, (8)—CN, (9) —CO₂R⁹, (10) —NR¹⁰R¹¹, (11) —SO₂R¹², (12) —CONR^(10a)R^(11a),(13) —OCO₂R⁹, and (14) —(NR^(10a))CO₂R⁹; R⁶ is selected from: (1)hydrogen, (2) —C₁₋₆alkyl or —C₃₋₆cycloalkyl which are unsubstituted orsubstituted with 1-7 substituents each independently selected from: (a)halo, (b) hydroxy, (c) —O—C₁₋₆alkyl, (d) —C₃₋₆cycloalkyl, (e) phenyl,which is unsubstituted or substituted with 1-5 substituents eachindependently selected from: (i) —C₁₋₆alkyl, (ii) —O—C₁₋₆alkyl, (iii)halo, (iv) hydroxy, and (v) trifluoromethyl, (f) —CO₂R⁹, (g) —NR¹⁰R¹¹,(h) —CONR¹⁰R¹¹, (i) —SO₂R¹², and (j) trifluoromethyl (3) phenyl orheterocycle, wherein heterocycle is selected from: pyridinyl,pyrimidinyl, pyrazinyl, thienyl, or morpholinyl, which phenyl orheterocycle is unsubstituted or substituted with 1-5 substituents eachindependently selected from: (a) —C₁₋₆alkyl, (b) —O—C₁₋₆alkyl, (c) halo,(d) hydroxy, and (e) trifluoromethyl; pharmaceutically acceptable saltthereof and individual enantiomers and diastereomers thereof.
 2. Thecompound of claim 1 having the formula Ia:

pharmaceutically acceptable salt thereof and individual enantiomers anddiastereomers thereof.
 3. The compound of claim 1 having the formula Ib:

pharmaceutically acceptable salt hereof and individual enantiomers anddiastereomers thereof.
 4. The compound of claim 1 having the formula Ic:

pharmaceutically acceptable salt thereof and individual enantiomers anddiastereomers thereof.
 5. The compound of claim 1 having the formula Id:

pharmaceutically acceptable salt thereof and individual enantiomers anddiastereomers thereof.
 6. The compound of claim 1 having the formula Ie:

pharmaceutically acceptable salt thereof and individual enantiomers anddiastereomers thereof.
 7. The compound of claim 1 wherein A¹ is selectedfrom CH₂ and —C(═O); A² is a bond; and A³ is a bond.
 8. The compound ofclaim 1 wherein A⁴ is selected from CH₂ and a bond; A⁵ is CH₂; A⁶ isCH₂; and A⁷ is selected from CH₂ and a bond.
 9. The compound of claim 1wherein B¹ is selected from

B⁴ is selected from

B² is selected from C(R¹)—, —CR¹R²—, and —C(═O)—; and B³ is selectedfrom ═C(H)—, —CH₂—, —C(═O)—, and a bond.
 10. The compound of claim 1wherein D¹ is selected from ═C(R¹)—, —CR¹R²—, —C(═O)—, and —N(R¹)—; andD² is selected from —CR¹R²— and —N(R¹)—.
 11. The compound of claim 1wherein E¹ is selected from: ═C(R⁴)—, —CR⁴R⁵—, ═N—, and —N(R⁴)—; E² isselected from

E³ is selected from: a bond, ═C(R⁴)—, —CR⁴R⁵—, ═N—; and —N(R⁴)—; E⁴ isselected from a bond and —CH₂—; and E⁵ is selected from ═C(R⁴)—,—CR⁴R⁵—, ═N— and —N(R⁴)—.
 12. The compound of claim 1 wherein G¹ is═C(R⁴)— and G² is ═C(R⁴)—.
 13. The compound of claim 1 wherein T isselected from ═C(R¹)— and ═N—; U is selected from ═C(R¹)— and ═N—; and Vis ═C(H)—.
 14. The compound of claim 1 wherein W is selected from abond, —CR¹R²— and —C(═O)—; X is selected from a bond, —CR¹R²—, and—C(═O)—; Y is selected from a bond, —CR¹R²—, and —C(═O)—; and Z isselected from a bond, —CR¹R²—, and —C(═O)—.
 15. The compound of claim 1wherein R¹ and R² are independently selected from: (1) hydrogen; (2)—C₁₋₆alkyl, which is unsubstituted or substituted with 1-5 substituentseach independently selected from: (a) halo, (b) hydroxy, (c)—O—C₁₋₆alkyl, which is unsubstituted or substituted with 1-3 fluoro, (d)—C₃₋₆cycloalkyl, (e) phenyl or heterocycle, wherein heterocycle isselected from: azetidinyl, imidazolyl, oxazolyl, pyridinyl, pyrimidinyl,pyrazinyl, piperidinyl, piperazinyl, pyrrolidinyl, thiazolyl, thienyl,triazolyl, tetrazolyl, tetrahydrofuryl, or morpholinyl, which phenyl orheterocycle is unsubstituted or substituted with 1-3 substituents eachindependently selected from: (i) —C₁₋₄alkyl, which is unsubstituted orsubstituted with 1-3 fluoro, (ii) —O—C₁₋₄alkyl, which is unsubstitutedor substituted with 1-3 fluoro, (iii) halo, (iv) hydroxy, (v)trifluoromethyl, and (vi) —OCF₃, (f) —CO₂R⁹, (g) —NR¹⁰R¹¹, (h)—CONR^(10a)R^(11a), (i) —(NR^(10a))CO₂R⁹, and (j)—(NR⁹)(CO)NR^(10a)R^(11a); (3) —C₃₋₆cycloalkyl, which is unsubstitutedor substituted with 1-3 substituents each independently selected from:(a) halo, (b) hydroxy, (c) —C₁₋₆alkyl, and (d) —O—C₁₋₆alkyl, (4) phenylor heterocycle, wherein heterocycle is selected from: pyridinyl,pyrimidinyl, pyrazinyl, thienyl, pyrrolidinyl, azetidinyl, thiazolyl,oxazolyl, isoxazolyl, imidazolyl, triazolyl, tetrazolyl, benzimidazolyl,benzoxazolyl, imidazolinyl, indolinyl, indolyl, quinolinyl,isoquinolinyl, tetrahydroquinolinyl, isoindolinyl,tetrahydroisoquinolinyl, 2-oxopiperazinyl, 2-oxopiperidinyl,2-oxopyrrolidinyl, quinazolinyl, tetrahydrofuryl, naphthyridinyl,quinoxalinyl, 1,3-dioxolanyl, oxadiazolyl, piperidinyl,tetrahydropyranyl, and morpholinyl, which phenyl or heterocycle isunsubstituted or substituted with 1-3 substituents each independentlyselected from: (a) —C₁₋₄alkyl, which is unsubstituted or substitutedwith 1-3 fluoro, (b) halo, (c) hydroxy, (d) —O—C₁₋₄alkyl, which isunsubstituted or substituted with 1-6 fluoro, (e) —C₃₋₆cycloalkyl, (g)—CO₂R⁹, (h) —NR¹⁰R¹¹, and (i) —CONR^(10a)R^(11a), (5) halo, (6) hydroxy,(7) —O—C₁₋₄alkyl, which is unsubstituted or substituted with 1-3 halo,(8) —CN, (9) —CO₂R⁹, (10) —NR¹⁰R¹¹, (11) —CONR^(10a)R^(11a), and (12)—(NR^(10a))CO₂R⁹.
 16. The compound of claim 1 wherein R¹ and R² areindependently selected from: (1) hydrogen; (2) —C₁₋₄alkyl, which isunsubstituted or substituted with 1-3 substituents each independentlyselected from: (a) halo, (b) —O—C₁₋₄alkyl, (c) phenyl or heterocycle,wherein heterocycle is selected from: azetidinyl, oxazolyl, pyridinyl,pyrimidinyl, pyrazinyl, piperidinyl, piperazinyl, pyrrolidinyl,tetrahydrofuryl, or morpholinyl, which phenyl or heterocycle isunsubstituted or substituted with 1-3 substituents each independentlyselected from: (i) —C₁₋₄alkyl, (ii) —O—C₁₋₄alkyl, (iii) halo, and (iv)hydroxy, (d) —CO₂R⁹, (e) —NR¹⁰R¹¹, (f) —CONR^(10a)R^(11a), (3)—C₃₋₆cycloalkyl, (4) phenyl or heterocycle, wherein heterocycle isselected from: pyridinyl, pyrimidinyl, pyrazinyl, pyrrolidinyl,azetidinyl, oxazolyl, imidazolyl, 2-oxopiperazinyl, 2-oxopiperidinyl,2-oxopyrrolidinyl, tetrahydrofuryl, oxadiazolyl, piperidinyl, andmorpholinyl, which phenyl or heterocycle is unsubstituted or substitutedwith 1-3 substituents each independently selected from: (a) —C₁₋₄alkyl,which is unsubstituted or substituted with 1-3 fluoro, (b) halo, (c)hydroxy, (d) —O—C₁₋₄alkyl, (e) —C₃₋₆cycloalkyl, (f) —NR¹⁰R¹¹, and (g)—CONR¹⁰R¹¹, (5) halo, (6) hydroxy, (7) —O—C₁₋₄alkyl, which isunsubstituted or substituted with 1-3 halo, (8) —CN, (9) —CO₂R⁹, (10)—NR¹⁰R¹¹, (11) —CONR^(10a)R^(11a), and (12) —(NR^(10a))CO₂R⁹. 17-23.(canceled)
 24. A compound selected from:

or a pharmaceutically acceptable salt thereof and individualstereoisomers thereof.
 25. A pharmaceutical composition which comprisesan inert carrier and the compound of claim 1, or a pharmaceuticallyacceptable salt thereof and individual enantiomers and diastereomersthereof.
 26. (canceled)
 27. A method for treating in a mammalian patientin need of such which comprises administering to the patient atherapeutically effective amount of the compound of claim 1, or apharmaceutically acceptable salt thereof and individual enantiomers anddiastereomers thereof.
 28. A method of treating headaches, said methodcomprising the co-administration, to a person in need of such treatment,of: a therapeutically effective amount of the compound of claim 1 or apharmaceutically acceptable salt thereof; and a therapeuticallyeffective amount of a second agent selected from serotonin agonists,analgesics, anti-inflamatory agents, anti-hypertensives andanticonvulsants.